Drug allergy: the mechanisms of development, symptoms, diagnostics, and treatment. Measures preventing the drug allergy
Lecture № 3
DRUG ALLERGY: the Mechanisms of Development,
Symptoms, Diagnostics, and Treatment.
Measures Preventing the Drug Allergy.
pharmacologic effects of a drug except:
● Therapeutic Failures,
● Intentional Overdosage,
● Abuse of the Drug, or
● Errors in Administration.
ADRs are categorized into:
Type A: predictable (75%) – dose dependent, related
to the known pharmacologic actions of the drug, and
occur in otherwise healthy individuals
Type B: unpredictable (25%) reactions - generally
dose independent, unrelated to the actions of
the drug, and occur
only in SUSCEPTIBLE INDIVIDUALS.
● Drug Intolerance
● Drug Idiosyncrasy
● Drug Allergy
● Pseudoallergic Reactions.
Drug allergy is a non-predictable immunologically
mediated ADR to a pharmaceutical and/or
formulation agent in a sensitized person.
Drug allergy differs from drug toxicity in many ways:
● The lesion produced by allergy is lower in incidence
● It is unpredictable;
● Prior exposure to the drug may cause sensitization;
● The lesion is dose independent and rash, fever,
eosinophilia and blood dyscrasias can occur.
Type I (Anaphylactic) reactions - Immediate hypersensitivity
reactions are IgE mediated:
Urticaria, Itching, Subepidermal Necrolysis – Lyell's syndrome,
Angioedema, Asthma, Rhinitis, Anaphylactic Shock.
Type II (Cytolytic) reactions are mediated by IgG or IgM:
Blood Transfusion Reactions, Haemolytic Disease of Newborns,
Autoimmune Haemolytic Anemia, Thrombocytopenia, Agranulocytosis,
Aplastic Anaemia, Haemolysis, Organ Damage (the liver, kidney,
muscle), Systemic Lupus Erythematosus and Some Drug Reactions.
Type III (Retarded) reactions are mediated by circulating antibodies
(predominantly mopping antibody, IgG):
Serum sickness - symptoms develop within 7-10 days and include
Urticaria, Lymphadenopathy, Myalgia, Arthralgia, Fever,
Polyarthritis Nodosa, Stevens-Johnson syndrome.
Systemic lupus erythematosus is an autoimmune disorder that may be
induced by Hydralazine, Novocainamide, Isoniazid and other drugs.
Type IV (Delayed hypersensitivity) reactions:
several hours or days after exposure to the antigenare cell-mediated through production of sensitized
T-lymphocytes carrying receptors for the antigen.
On contact with antigen these T cells produce
limphokines which attract granulocytes and generate
an inflammatory response, e.g., contact dermatitis,
some rashes, fever, photosensitization.
to the surface of mast cells and basophils, leading
to their degranulation and liberation of histamine
and other mediators:
●Those that Vascular Permeability and contract
smooth muscles: Histamine, PAF, SRS-A, Bradykinin.
●Those that are chemotactic for or activate other
pro-inflammatory cells: Leukotriene B4,
Eosinophil and Neutrophil Chemotactic Factors.
●Those that modulate the release of other
mediators: Bradykinin, PAF, Prostaglandins.
●Those which cause termination of the immune
7. DRUG ALLERGYThe most dangerous type of ADRs.
45% reports of AR/SE of drugs in town of
900 reports of allergic reactions on drugs
(36% reports of AR/SE of drugs) in Ukraine
Latent forms of hypersensitivity to drugs –
in 10-15% world population and
20% healthy people (according to WHO).
8. Allergic Anamnesis IgnoringAnalgin, Aspirin, Ampicillin were administered in
patients with allergic anamnesis (sometimes with other
Severe allergic reactions were observed –
Anaphylactic Shock, Quincke‘s edema, Toxic Dermatitis.
Allergic reacitons on Flemoxin and Grunamox in
patients with drug allergy to Amoxicillin
Allergic reacitons on Solpadein the active substance
of which is Paracetamole.
The main reason of manifestation – absence of
knowledge of numerous trade names of
Generic Drugs containing the Same Active Agents.
(Cytotoxic, Helper and Suppressor) and their
responses constitute Cell Mediated Immunity (CMI).
They regulate Humoral Immunity, B lymphocyte function.
T-cells carrying CD4+ antigen are responsible for
the HELPER function and the delayed hypersensitivity.
Th1 cells enhance CMI but inhibit Humoral Immunity.
Th2 cells have the opposite effect.
T-cells carrying CD8+ antigen are mainly responsible
for the CYTOTOXIC and SUPPRESSOR functions.
Examples of Agents
Urticaria, angioedema, bronchospasm, β-Lactam Antibiotics,
Hemolytic anemia, thrombocytopenia, Penicillin, Quinine,
Cutaneous or Visceral Vasculitis
Drug Rash, Fever, Eosinophilia,
hepatic dysfunction, lymphadenopathy Sulfonamides, Allopurinol
Cutaneous Druginduced Lupus
Erythematous / Scaly Plaques
Hepatitis, Cholestatic Jaundice
Ca2+ channel blockers,
DRESS: Drug Rash with Eosinophilia and Systemic Symptoms;
TEN - Toxic Epidermal Necrolysis
Mast cells Degranulation
Local Anaphylaxis (ATOPY)
Stabilize Mast Cell Membrane
(Cromolyn, Ketotifen, Ephedrine)
Late Phase Inhibitors
(Hay, fever) (Pain, Diarrhea) (Asthma) (Eczema)
12. Aspirin and other NSAIDs are reported to account for 21-25% of all Adverse Drug ReactionsIntake of:
produced severe Bronchoobstructive Syndrome in
patients with Aspirin Asthma.
Aspirin-induced asthma refers to the development of
acute bronchoconstriction, profuse rhinorrhea and
skin flushing in asthmatic individuals following
the ingestion of aspirin.
2 main pathways of the metabolism of Arachidonic Acid
The COX pathway converts Arachidonic Acid to
Prostaglandins, Prostacyclin and Thromboxane A.
Attacks of asthma precipitated by Aspirin like drugs are due
to the inhibition of COX in airways of the sensitive patients:
the Bronchoconstrictor PgF at the expense of
the Bronchodilator PgE2 due to altered COX response.
The LO Pathway converts Arachidonic Acid to
Leukotriene A4 (LT A4) further hydroxylated to LT B4.
LT B4 is a potent chemotactic agent.
The Sulphidopeptide Leukotrienes LT C4, LT D4 and LT E4 are
constrictors of the smooth muscle of the airway
Aspirin-induced asthma may relate to the inhibition of COX,
resulting in the "shunting" of Arachidonic Acid cascade to
the 5- Lipoxygenase pathway.
1. Drugs Stabilizing Mast Cell Membrane:
Glucocorticoids: Prednisolone, Hydrocortisone
Antihistamine H1 : Ketotifen
a Mast cell stabilizer: Cromolyn
β-adrenomimetics: Adrenaline, Ephedrine
Methylxanthines: Euphylline (Aminophylline)
2. Antihistamine H1 agents: Dimedrol, Diprazine, Loratadine
3. Agents eliminating generalized symptoms of immediate allergic
Methylxanthines: Euphylline, Theophylline
Ca2+ preparations: Calcium chloride, Ca2+ gluconate
4. Agents decreasing tissue damage: Glucocorticoids
15. GLUCOCORTICOIDS (GCs)1. Short-acting: Hydrocortisone acetate
3. Long-acting: Betametasone,
OINTMENTS for local use - Fluorine-containing:
AEROSOLS or POWDERS FOR INHALATIONS:
Steroid hormones are lipid soluble and cross cell membranes
Once inside the cell, the hormone molecules bind with specific
The hormone–receptor complex enters the nucleus of the cell
where it activates Gene Expression –
nucleic acids (DNA and RNA) and
the Genetic Code to synthesize
and immune response:
GCs change Gene Expression:
Production of prostanoids owing to
Decreased Expression of COX-2
Generation of cytokines –
IL 1-6, IL-8, TNF- and cell adhesion factor –
through inhibition of transcription of
the relevant genes
Complement components in the plasma
Generation of induced NO
Histamine release from basophils
18. Adverse effects of GCs: Cushing’s syndrome:Moon face, with red cheeks
Thin arms and legs: muscle wasting
BP, Itracranial Hypertension
Thinning of skin
Increased abdominal fat
Depression or emotional lability
Avascular necrosis of femoral head
Nedocromil (aerosol: 2 mg/dose) stabilize mast cells and
prevent the release of bronchoconstrictive and inflammatory
substances when mast cells are confronted with allergens
and other stimuli.
They stabilize the mast cell membrane and inhibit release of
the mediators of Type I allergic reaction, including: histamine
and Slow Reacting Substance of Anaphylaxis (SRS-A) from
sensitized must cells.
Pretreatment with cromolyn blocks allergen-induced and
exercise-induced bronchoconstriction by acting on
inflammatory cells such as eosinophils.
(H1) and mast cell stabilizer.
● It inhibits stimulation of immunogenic and inflammatory
cells (mast cells, macrophages, eosinophils, lymphocytes,
neutrophils) and mediator release.
● It is believed to inhibit airway inflammation induced by
platelet activating factor (PAF).
Ketotifen prevents bronchial asthma attacks.
● It also produces relief in patients with rhinitis, atopic
dermatitis, conjunctivitis, urticaria, food allergy, migraine
Adverse effects: sedation, dry mouth, dizziness, nausea,
Exocrine excretion => Nasal and Bronchial mucus
Bronchial smooth muscle constriction => bronchospasm
Intestinal smooth muscle contraction =>
cramps and diarrhea
Sensory nerve endings: itch and pain
Stomach: Stimulation of Gastric Hydrochloric Acid Secretion
H1- and H2-Receptors:
Cardiovascular system: BP and HR
‘Triple Response’ – Wheal formation, Reddening, Flare
I GENERATION (SEDATIVE):
II GENERATION (NON-SEDATIVE):
III GENERATION (ACTIVE METABOLITES):
Telfast (Fexofenadine) 23
Block the actions of histamine by reversible competitive
antagonism at the H1-receptor
Antagonist effects at other receptors:
M - Cholinoceptors
α1 - Adrenoreceptors
5-Hydrohytryptamine (5-HT) receptors
Diprazin Dimedrol Suprastin Diazolin
competes to H1 receptors on the smooth muscle of
the bronchi, GIT, uterus, and large blood vessels.
By binding to receptors, suppresses histamine-induced
allergic symptoms, even though it does not prevent its
Central antimuscarinic actions is responsible for antivertigo,
antiemetic, and antidyskinetic action.
blocks cardiac K+ channels, prolongs Q-T and
has occasionally produced Polymorphic Ventricular Tachycardia.
The risk is increased in liver disease or when inhibitors of CYP3A4 are
administered concurrently – because larger amounts of unchanged drug
reach systemic circulation.
Erythromycin, Clarithromycin, Ketoconazole and Itraconazole
are the drugs precipitating their
cardiotoxicity as they block
microsomal CYP-450 enzymes.
Because of this risk,
Terfenadine has been withdrawn
by most manufactures.
Clinical use: allergic rhinitis
Adrenaline h/ch - 0.1% sol.
0.3-0,5-1 ml in 2-3 ml of 0.9%
NCl solution SC in the region
of injection and around it,
SL or intratracheal instillation,
Mesaton 1% sol. 1-2 ml IV in
0.9% NaCl solution
Noradrenaline h/t 0.2% in
0.9% NCl solution IV infusion
Prednisolone 3% solution
30-90 mg and more IV
in 0.9% NCl solution
0.025% 1-2 ml IV in
0.9% NCl solution
Euphylline 2.4% sol.
3-5-10 ml IV
in 0.9% NaCl solution
1000 000 UA in 2
ml of 0.9% NaCl solution in the
region of injection
Oxygen inhalation for
hypoxia control or
I. IMMUNOSUPRESSANTS - suppressing mainly
1.Inhibitors of IL-2 production or action:
2.Inhibitors of cytokine gene expression:
3. Antitumor Cytotoxic Agents:
a) Alkylating agents: Cyclophosphan
b) Antimetabolites: Azathioprine, Mercaptopurine,
4.Blockers of the T-cell surface molecules involved in signaling Monoclonal Antibodies: Basiliximab
Delayed Type Hypersensitivity Reactions:
II. Drugs decreasing tissue damage –