Adverse Drug Reactions

• Unwanted effects and adverse drug reactions include definitions, sources of adverse drug reactions, allergy in response to drugs, effects of prolonged administration (chronic organ toxicity), and adverse effects on reproduction.

Definitions

• Side effects, adverse drug reactions (ADR), toxicity, secondary effects, intolerance, and idiosyncrasy are types of unwanted effects and adverse drug reactions.
• Many unwanted effects of drugs are medically trivial.
• The term "side-effects" is widely used for minor reactions that occur at normal therapeutic doses and are predictable and usually dose-related.
• Adverse drug reaction (ADR) refers to harmful or seriously unpleasant effects occurring at therapeutic doses that call for dose reduction, drug withdrawal, and/or forecast future administration hazards.
• Adverse "reaction" is synonymous with adverse "effect," but an "effect" relates to the drug, and a "reaction" to the patient.
• Both terms should be distinguished from an adverse "event," which is an adverse happening during drug exposure without assuming its cause.
• Toxicity implies a direct action of the drug, often at high dose, damaging cells, such as liver damage from paracetamol overdose or eighth cranial nerve damage from gentamicin.
• All drugs are toxic in overdose, which can be absolute or relative.
• In the latter case, an ordinary dose may be toxic due to an underlying abnormality in the patient, such as kidney disease.
• Secondary effects are the indirect consequences of a primary drug action, such as vitamin deficiency or opportunistic infection in patients whose normal bowel flora has been altered by antimicrobials, or diuretics-induced hypokalemia causing digoxin toxicity.
• Intolerance means a low threshold to the normal pharmacodynamic action of a drug.
• Individuals vary greatly in their susceptibility to drugs.
• Those at one extreme of the normal distribution curve are intolerant of the drugs, while those at the other end are tolerant.
• Idiosyncrasy is an inherent qualitative abnormal reaction to a drug, usually due to a genetic abnormality, e.g., porphyria.

Sources of Adverse Drug Reactions

• A patient may be predisposed to an ADR by age, sex, genetic constitution, known allergy tendency, disease of drug eliminating organs, and social habits like tobacco, alcohol, or recreational drug use.
• The very old and young are liable to be intolerant to many drugs because their mechanisms for disposing of the drugs in the body are less efficient.
• Females are more likely to experience adverse reactions to certain drugs, e.g., mefloquine (neuropsychiatric effects).
• Drug metabolism may be increased by hepatic enzyme induction from insecticide accumulation, e.g., dicophane (DDT), and from alcohol or tobacco use.
• Smokers require a higher dose of theophylline.
• Antimicrobials used in animal feeds have raised concern about the spread of resistant bacteria.
• Penicillin in the air of hospitals or in milk may cause allergy.

Allergy in Response to Drugs

• Allergic reactions to drugs result from the interaction of a drug or metabolite (or a non-drug element in the formulation) with the patient and disease, and subsequent re-exposure.
• The drug causes the formation of tissue-sensitizing immunoglobulin IgE antibodies that are fixed to mast cells or leucocytes.
• On subsequent administration, the allergen (conjugate of drug or metabolite with tissue protein) reacts with these antibodies, activating but not damaging the cell to which they are fixed and causing the release of pharmacologically active substances like histamine, leukotrienes, prostaglandins, and platelet activating factor.
• This causes effects such as urticaria, anaphylactic shock, and asthma.
• Allergy develops within minutes and lasts for 1-2 hours, and can be fatal.
• Type I reactions: Immediate or Anaphylactic type includes examples such as penicillin, streptokinase, and insulin.
• The drug or metabolite combines with a protein in the body, so the body no longer recognizes the protein as self, treats it as a foreign protein, and forms antibodies.
• IgG and IgM combine with the antigen and activate complement which damages cells, e.g., penicillin- or methyldopa-induced hemolytic anemia.
• Type II reactions are antibody-dependent and cytotoxic.
• Antigen and antibody form large complexes and activate complement, damaging or blocking small blood vessels.
• Leucocytes attracted to the site of reaction engulf the immune complexes and release pharmacologically active substances (including lysosomal enzymes), starting an inflammatory process.
• These Type III reactions include serum sickness, glomerulonephritis, vasculitis, and pulmonary disease.
• In Type IV reactions, antigen-specific receptors develop on T lymphocytes. Subsequent administration leads to a local or tissue allergic reaction, e.g., contact dermatitis.
• Cross-allergy within a drug group is usual, e.g., penicillins.
• Controversy exists regarding the extent of cross-reaction with cephalosporins.
• When allergy to a particular drug is established, select a substitute from a chemically different group.
• Patients with allergic diseases (atopy), e.g., eczema, are more likely to develop allergy to drugs.

Distinctive Features of Allergic Reactions

• Lack of correlation with known pharmacological properties of the drug.
• Lack of linear relation with drug dose, as very small doses may cause very severe effects.
• Characteristics include rashes, angioedema, serum sickness syndrome, anaphylaxis, or asthma; characteristics of classic protein allergy.
• An induction period on primary exposure is required, but not on re-exposure.
• Disappearance occurs upon cessation of administration and reappearance upon re-exposure to a small dose.
• Occurrence in only a minority of patients receiving the drug.
• Possible response to desensitization.

Principal Clinical Manifestations and Treatment

• Urticarial rashes and angioedema, classified as Type I and III reactions, are the commonest type of drug allergy, often generalized but worst at the administration site.
• Eyelids, lips, and face are usually most affected, with usual itching.
• Oedema of the larynx is rare but may be fatal.
• Treatment includes adrenaline/epinephrine, ephedrine, H1-receptor antihistamine, and adrenal steroid.
• Non-urticarial rashes (types I, II, IV) occur in great variety, frequently with weeping exudative lesions; determining if a rash is due to a drug is often difficult
• Apart from stopping the drug, the treatment is non-specific.
• An adrenal steroid should be used in severe cases.
• Skin sensitization to antimicrobials may be very troublesome, especially among those who handle them.
• Diseases of the lymphoid system, such as infectious mononucleosis and lymphoma, are associated with an increased incidence (>40%) of a characteristic maculopapular, sometimes purpuric, rash which is probably allergic, when an aminopenicillin (ampicillin, amoxicillin) is taken.
• Patients may not be allergic to other penicillins, and erythromycin may cause a similar reaction
• Anaphylactic shock (type 1) occurs with penicillin, anaesthetics (intravenous), iodine-containing radiocontrast media, and various other drugs.
• A severe fall in blood pressure occurs, with bronchoconstriction, angioedema (including larynx), and sometimes death due to loss of fluid from the intravascular compartment and respiratory obstruction, usually suddenly within an hour after drug administration, or within minutes if given intravenously.
• In adults, 500 micrograms of adrenaline/epinephrine injection (0.5 mL of the 1 in 1000 solution) should be given intramuscularly to raise blood pressure and dilate the bronchi.
• Vasoconstriction renders the subcutaneous route less effective.
• If there is no clinical improvement, further intramuscular injections of adrenaline/epinephrine 500 micrograms should be given at 5-minute intervals according to blood pressure, pulse, and respiration.
• If shock is profound, cardiopulmonary resuscitation/advanced life support is necessary.
• Consider 1:10,000 adrenaline/epinephrine by slow intravenous infusion at 100 micrograms/min (1 mL/min of the dilute 1 in 10,000 solution over 5 minutes), preferably with continuous ECG monitoring, stopping when a response is obtained.
• This procedure is hazardous and should be undertaken only by an experienced practitioner who can obtain immediate intravenous access and where other resuscitation facilities are available.
• Adrenaline/epinephrine should be accompanied by an H1-receptor antihistamine, e.g., chlorphenamine 10–20 mg intramuscularly or by slow intravenous injection, and by hydrocortisone 200–500 mg intramuscularly or by slow intravenous injection.
• The adrenal steroid acts by reducing vascular permeability and by suppressing further response to the antigen-antibody reaction.
• In severe anaphylaxis, hypotension is due to vasodilation and loss of circulating volume through leaky capillaries.
• 1–2 L of plasma substitute should be infused rapidly if there is no response to drug treatment. Crystalloid may be safer than colloid, which causes more allergic reactions.
• A b2-adrenoceptor agonist is appropriate where bronchospasm is severe and does not respond rapidly to other treatment.
• Noradrenaline/norepinephrine lacks any useful bronchodilator action.
• Where susceptibility to anaphylaxis is known, e.g., in patients with allergy to bee or wasp stings, preventive self-management is feasible.
• Patients are taught to administer adrenaline/epinephrine intramuscularly from a pre-filled syringe (EpiPen Auto-injector, delivering adrenaline/epinephrine 300 micrograms per dose).
• Pulmonary reactions include asthma (type I) caused by aspirin and other non-steroidal anti-inflammatory drugs, which can cause bronchoconstriction, not exclusive to asthmatic patients.
• Abnormal levels of leukotrienes synthesis following blockade of cyclo-oxygenase may be causal.
• Cough due to angiotensin-converting enzyme inhibitors is another such reaction; in this case, pro-inflammatory peptides such as bradykinin accumulate and trigger cough.
• Other types of pulmonary reaction (type III) include syndromes resembling acute and chronic lung infections, pneumonitis, fibrosis, and eosinophilia.
• Serum sickness syndrome (type III) occurs about 1-3 weeks after administration and is treated by an adrenal steroid, especially if there is urticaria.

Blood Disorders

• Thrombocytopenia (type II, but also pseudo-allergic) may occur after exposure to many drugs, including gold, quinine, quinidine, rifampicin, heparin, thionamide derivatives, thiazide diuretics, sulphonamides, oestrogens, and indometacin. Adrenal steroids may help.
• Granulocytopenia (type II, but also pseudo-allergic), sometimes leading to agranulocytosis, is a very serious reaction that may occur with many drugs, e.g., clozapine, carbamazepine, carbimazole, chloramphenicol, sulphonamides (including diuretic and hypoglycaemic derivatives), colchicine, and gold.
• Aplastic anaemia (type II, but not always allergic).
• Causal agents include chloramphenicol, sulphonamidesand derivatives (diuretics, antidiabetics), gold, penicillamine, allopurinol, felbamate, phenothiazines, and some insecticides, e.g., dicophane (DDT).
• In the case of chloramphenicol, bone marrow depression is a normal pharmacodynamic effect.
• Aplastic anaemia may also be due to idiosyncrasy or allergy.
• Death occurs in about 50% of cases, and treatment is as for agranulocytosis, with blood transfusion.
• Haemolysis of all kinds is included for convenience, in three principal categories.
• Allergy (type II) occurs with penicillins, methyldopa, levodopa, quinine, quinidine, sulfasalazine, and organic antimony.
• Drug protein-antigen/antibody interaction is present for some, involving erythrocytes only casually, a "true innocent bystander" phenomenon.
• Dose-related pharmacodynamic action on normal cells, e.g., lead, benzene, phenylhydrazine, chlorates (weedkiller), methyl chloride (refrigerant), and snake venoms.
• Idiosyncrasy: Precipitation of haemolytic crisis may occur with the above drugs in rare genetic haemoglobinopathies.
• Treatment is to withdraw the drug, and an adrenal steroid is useful in severe cases if the mechanism is immunological. Blood transfusion may be needed.
• Hepatitis and cholestatic jaundice are sometimes allergic, especially beyond 55 years of age. Adrenal steroid may be useful treatment.
• Nephropathy of various kinds (types II, III), as well as damage to other organs, e.g. myocarditis, also occurs.

Diagnosis of Drug Allergy

• Simple patch skin testing is naturally most useful in diagnosing contact dermatitis but is unreliable for other allergies.
• Skin prick tests are helpful in specialist hands for diagnosing IgE-dependent drug reactions, notably due to penicillin, cephalosporins, muscle relaxants, thiopental, streptokinase, cisplatin, insulin, and latex.
• These agents can cause anaphylactic shock.

Desensitization

• Once patients become allergic to a drug, they should never again receive it.
• In those who suffer an IgE-mediated reaction to penicillin in hospital and need the drug, desensitisation may be considered.
• People can be desensitized by giving small amounts of allergen, increased gradually (usually every few hours) until a normal dose is tolerated.
• If a patient claims to be allergic to a drug, it should not be given without careful enquiry that may also include testing.

Pseudo-Allergic Reactions

• Pseudo-allergic effects mimicking type I reactions are called anaphylactoid.
• They occur with aspirin and other non-steroidal anti-inflammatory drugs, with N-acetylcysteine (indirect action), corticotropin (direct histamine release), intravenous anaesthetics, and a variety of other drugs given intravenously (morphine, tubocurarine, dextran, radiographic contrast media) and inhaled (cromoglicate).
• Type II reactions are mimicked by haemolysis induced by drugs (some antimalarials, sulphonamides, and oxidizing agents) and food (broad beans) in subjects with inherited abnormalities of erythrocyte enzymes or haemoglobin.
• Type III reactions are mimicked by nitrofurantoin (pneumonitis) and penicillamine (nephropathy).
• Lupus erythematosus due to drugs (procainamide, isoniazid, phenytoin) may be pseudo-allergic.

Chronic Organ Toxicity

• Eye: Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines, and alkylating agents.
• Corneal opacities occur with phenothiazines and chloroquine.
• Retinal injury develops with thioridazine (particularly, of the antipsychotics), chloroquine, and indometacin, and visual field defects with vigabatrin.
• Nervous system: Tardive dyskinesias occur with neuroleptics; polyneuritis with metronidazole; optic neuritis with ethambutol.
• Lung: Amiodarone may cause pulmonary fibrosis. Sulfasalazine is associated with fibrosing alveolitis.
• Kidney: Gold salts may cause nephropathy; see also analgesic nephropathy.
• Liver: Methotrexate may cause liver damage and hepatic fibrosis; amiodarone may induce steatohepatitis (fatty liver).

Carcinogenesis

• Alteration of DNA (genotoxicity, mutagenicity).
• Many chemicals or metabolites act by causing mutations, activating oncogenes.
• Those substances used as medicines include griseofulvin and alkylating cytotoxics.
• Leukaemias and lymphomas are the most common malignancies.
• Malignancies develop following immunosuppression.
• Immunosuppressed patients develop cancer e.g. after organ transplantation and cancer chemotherapy.
• There is a high incidence of lymphoid neoplasm: chlorambucil, melphalan and thiotepa present particular high risks.
• Immunosuppression used in treatment e.g. rheumatoid arthritis, also increases the incidence of neoplasms.
• Hormonal.
• Long-term use of oestrogen replacement in postmenopausal women induces endometrial cancer.
• Both suppress and enchance cancers can be caused by combined oestrogen/progestogen oral contraceptives

Adverse Effects on Reproduction

• Drugs may act on the embryo and fetus, either directly or indirectly.
• Directly affecting cell division, enzymes, or protein synthesis is a potential teratogen, e.g., many antimicrobials.
• Indirectly non the uterus (vasoconstrictors reduce blood supply and cause fetal anoxia, misoprostol causes uterine contraction leading to abortion) on the mother's hormone balance.
• During early pregnancy (during the first week after fertilisation) exposure to antimetabolites, misoprostol, ergot alkaloids, or diethylstilbestrol can cause abortion.
• The most vulnerable period for major anatomical abnormality is during organogenesis.
• Organogenesis typically occurs during weeks 2–8of intrauterine life.
• Selective interference due to the teratogen leads to major anamotical abnormalities.
• Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, sodium valproate, angiotensin-converting enzyme inhibitors, and isotretinoin.
• Selective interference can produce characteristic anatomical abnormalities; the phocomelia(flipper-like) limb.
• During late pregnancy organs are well-formed so effects won't cause gross anatomical problems
• Hormones, androgens or progestogen can cause fetal masculinisation; iodide and antithyroid drugs in high dose can cause fetal goitre, lithium; tetracyclines can interfere with tooth and bone development.
• ACE inhibitors are associated with renal tubular dysgenesisand a skull ossification defect. Tobacco smoking retards fetal growth

Reproduction

• Chloroquine and chlorpromazine are highly concentrated in the fetal eye causing retinopathy, avoid in pregnancy
• Drugs given to the mother just prior to labour can cause postnatal effects.CNS depressants may persist in and affect the baby for days after birth. Vasoconstrictors can cause fetal distress by reducing uterine blood supply; b2-adrenoceptor blockers may impair fetal response to hypoxia; sulphonamides displace bilirubin from plasma protein risk of kernicterus. Bab ies born to mothers dependent on opioids may show a physical withdrawal syndrome.
• Impotence may occur affecting autonomic sympathetic function, e.g. many antihypertensives, also related sperm quality.
• Spermatogenesis is reduced by a number of drugs sulphsalizine
• Also can lead to cytotixic and cancer drugs
• Causation of birth defects due to abnormal sperm remains uncertain.

Causative Agents

• Some phototoxic agents include NSAIDs, Quinolones, amiodarone,furasamide, tetracycline sulfonamides, antimetabolite agents. Some photoallergic agents include NSAIDS, chloroquine,. Muroquinolones, statins, ACEinhibitors, calcium channel blocker, anticancer agents, topical treatment like antiseptics, cosmatics.

Aspirin-Exacerbated Respiratory Disease

• People with AERD usually have asthma, nasal congestion and recurrent nasal polyps, and their symptoms often do not respond to conventional treatments.
• AERD develop reactions to aspirin and other NSAID, causes frontal headaches/sinus pain respiratory symptoms (increased nasal congestion) or lower respiratory symptoms (cough, wheezing, chest tightness). but they can also induce skin flushing, rash, abdominal pain and occasionally vomiting.
• 75% of AERD patients mild-to-moderate respiratory reactions when they alcohol.reactions consume one glass of alcohol

Samter's Triad

• Aspirin-exacerbated respiratory disease (AERD), known as Samter's Traid, includes a chronic medical with three clinical features: asthma, sinus disease with recurrent nasal polyps, sensitivity to aspirin and other non-steroidal anti-inflammatory drugs that inhibit enzyme cyclooxygenase -1.
• 9% of all adukltsd with asthma and 30% patientis of all with asthma have ARD with 20-50 age
• Reactions manifest as respiratory reaction eating/inhaling NSAID's

Mechanism/Example Reaction Types

Type A (Augmented)

• The reaction is predicted from known drug phramacology and dependent on dose.

Type B (Bizarre)

• These reactions are not dependenton dose and not predicted from knwon phramcology

Type C (Chemical/Chronic)

• Related to chemical structure and its metabolism of drug example is hepatotoxicity

Type D (Delayed)

• Appear with treatment lasting years (delayed)

Type E (End of treatment)

• Occur with drug withdrawl