Adverse Drug Reactions

Adverse events following medical therapies are common. The term ‘adverse reaction’ is preferred by doctors over the more commonly used term ‘side effect’. This is because side effect implies that the effects are not explained by the pharmacological actions of the drug. Studies have shown that between 5% and 30% of all patients receiving medical therapies develop an adverse event. In many cases, it is not known what the underlying mechanism is for these adverse events, thus it is difficult to prevent recurrence in the future. This article will discuss what is known about adverse drug events and outline an approach for investigating them and predicting the likelihood of a recurrence. 

 

Adverse Drug Reaction Definitions

Adverse drug reaction (ADR) is a term used to describe the unwanted, negative consequences of drug therapy. Our immune system is a set of mechanisms that work to protect us from infection by identifying and destroying pathogens. The term drug hypersensitivity is used to describe any drug reaction that our immune system mounts unnecessarily. Drug allergy is restricted specifically to a reaction that occurs when special group of antibodies (Ig E) are activated. These antibodies are large, Y shaped proteins used by the immune system to recognise and destroy foreign bodies such as bacteria and viruses. (Learn more about the immune system.)

Classification of Adverse Drug Reactions

There are many ways of classifying ADRs – these are outlined in Table 1. The causes of ADRs can be divided into those mediated by our immune system and those that aren’t. The majority (75-80%) are type A (ie pharmacologically mediated) and are caused by non-immunologic effects. Immune mediated reactions account for 5-10% of all ADRs and are generally classified from Type 1 to Type 4, depending on the immune mechanism involved (see Table 2). Pseudoallergic or anaphylactoid reactions (ie reactions resembling immediate hypersensitivity reactions but are not mediated by allergen-IgE interaction) occur when a particular type of cell – the mast cell, (responsible primarily for becoming activated in allergy and anaphylaxis), is activated. Drugs such as opiates (a group of pain medications), vancomycin (a type of antibiotic) and radiocontrast media can trigger these reactions. These reactions may be hard to tell apart from true Ig E mediated reactions (also known as Type 1 sensitivity). In addition there are other specific drug hypersensitivity syndromes caused by non-IgE immune mechanisms (see Table 3).

Host Factors Influencing Adeverse Drug Reactions

Adverse reactions are known to be more common in older persons and in females. Recently another important factor has been identified – the HLA type of the individual patient plays a vital role. The HLA is a group of genes that encodes a group of proteins present on the surface of cells. HLA are involved in presenting foreign materials to the immune system. People who possess certain HLAs have a higher risk of ADRs with particular drugs (see Table 4). This is important to be aware of because the risk of an ADR with certain drugs can be reduced if you avoid giving the drug to patients with a high risk HLA.

Drug Factors Influencing Adverse Drug Reactions

Certain classes of drugs have a high incidence of adverse events. These include the nonsteroidal anti-inflammatory drugs (NSAIDS), antimicrobials (drugs helping fight bacteria), anticonvulsants (used to help control epilepsy), anaesthetic agents (An agent that causes loss of sensation with or without the loss of consciousness) and drugs that affect the muscles and nerves. You may be aware of recently published adverse events including the risk of cardiovascular disease (affecting the heart and blood vessels) with selective cox2 inhibitors, changes in the muscles with statins, angioedema (an allergic skin reaction characterized by patches of well defined swelling) with ACE inhibitors and angiotensin II antagonists, and lipid changes with antiretrovirals. There is convincing evidence that drugs associated with a high incidence of hypersensitive reactions are converted to products that can stimulate an immune mediated response in sensitive individuals. The way the drug is administered also influences the likelihood of an adverse event and its severity. Drugs applied to the skin are more likely to sensitize a patient to allergic reactions than drugs administered by injection or into the veins, and least often with the oral route. Intravenous administration gives rise to more severe reactions.

Diagnosis of an Adverse Drug Reaction

  • Clinical HIstory

When evaluating the cause of an ADR, the doctor may ask some of the following questions. These include: any clinical symptoms experienced and their timing and duration in relation to drug exposure. The most serious clinical manifestation is anaphylaxis – a severe allergic response. This involves a drop in blood pressure, spasm of the airways in the lungs, swelling of the tissues within the skin and possibly collapse of the heart and blood vessels. These reactions occur within a short time of taking the drug (usually less than 3 hours) and are caused by Type I hypersensitivity (antibody mediated reactions). Drugs more commonly associated with these reactions are antibiotics, radiocontrast media, anaesthetic drugs, enzymes, cisplatin, insulin and latex. Dermatological skin changes are the most common side effect of many drugs. Table 5 summarises the common skin manifestations and their mechanisms. Other clinical manifestations are summarised in Table 6. Studies have shown the value of clinical history in differentiating drug allergy from other forms of adverse drug reactions. Two studies involving 638 and 319 patients who were referred to an allergy clinic for possible penicillin allergy were divided into three groups based on clinical history. In patients with a history suggestive of penicillin allergy, the likelihood of a positive skin test was 72.2% and 14.1%. In a second group with only a vague history of drug allergy the incidence of positive skin tests was 14.1% and 6.7%. In the third group with an unconvincing history of drug allergy only 0.9% and 0% were positive on skin testing. This area, however, is controversial with other studies providing conflicting data. Some experts therefore recommend that all patients with any history of penicillin allergy should be skin tested prior to receiving penicillin.

  • Laboratory Investigations

Tests to determine possible ADRs which are mediated by the immune system include specific assays to measure the levels of antibodies present and also some skin tests. The diagnosis of drug allergy or hypersensitivity can be difficult and may require the input of a clinical specialist called an immunologist. The benefits of making an accurate diagnosis of an ADR include: 1.) Dangerous re- administration of drugs can be avoided 2.) Incorrect diagnosis are not made, allowing effective and inexpensive first line drugs to be administered. This avoids increased costs and the use of less efficacious second- line drugs and generation of antibiotic resistance. Testing in drug allergy clinics allows alternative drugs to be identified if required. If no alternative is available, a process called desensitisation can be performed – this involves gradual, repeated exposure to the allergic compound. Eventually, the immune system becomes tolerant of the compound and tolerance is maintained only for the course of therapy.

Treating an Adverse Drug Reaction

The most important decision for all suspected adverse drug reactions is to discontinue the suspected drug. In patients who are on multiple medications, the decision to stop the drugs must be weighed up between the need for the drug and its likelihood of causing the observed adverse effects. In suspected systemic Type I or anaphylactoid reactions the drug of choice to treat this ADR is adrenaline. It may be given as an injection into the muscle without delay, as early administration leads to better outcomes25. Another way of giving adrenaline is intravenously, through the veins, but this is only used in advanced, life threatening cases that fail to respond to adrenaline injections. Bronchodilators and systemic corticosteroids can also be used when treating allergic reactions, but administration of these should not delay the administration of adrenaline if required. Care should be taken with IV Phenergen (an antihistamine) because irritation of the veins can occur.

 

 

Conclusions

A better understanding of the mechanisms underlying an ADR is important in drug development and in patient care. If we can avoid drugs metabolised by certain metabolic or enzymatic pathways, this will help prevent the creation of reactive metabolites responsible for many drug hypersensitivity reactions. In patient care factors such age, sex, HLA type, kidney and liver function may be considered by the GP, in deciding drug therapy and drug doses. In the event of an ADR occurring it is important to attempt to determine the underlying mechanism in order to avoid a repeat incidence in the future. It must be emphasised that options for investigating ADRs are likely to expand rapidly due to future research in this important area.

Table 1: Classification of Adverse Drug Reactions

Type Name /Mechanism
Type A Pharmacologically predicted – ie due to actions of the drug itself, but which occur in excess.
Type B Idiosyncratic and Unpredictable(Includes drug allergy)
Type C Arising from Chronic (long term) use
Type D Delayed Toxicity
Type E Drug-drug interactions
Type F Failure of therapy

Table 2: Gell and Coombs Classification of Drug Hypersensitivity reactions

Immune Reaction Mechanism
Type I Antibody (Ig E) mediated
Type II Cytotoxic
Type III Drug-antibody complexes are deposited in the tissues
Type IV A delayed reaction occurring when drug molecules are presented to special cells called T cells, which are responsible for mediating an inflammatory response

Table 3: Specific Drug Hypersensitivity Syndromes caused by Non-IgE Immune Mechanisms

Causative Drug Syndrome
Hydralazine Procainamide Lupus like syndrome (Antibodies are produced inappropriately, cause swelling and damage to blood vessels in many organs)
Carbamazepine Phenytoin Anticonvulsant hypersensitivity syndrome (Characterised by fever, rash, hepatitis (inflammation of the liver) and other organ abnormalities)
Sulphonamides Anticonvulsants Stevens-Johnson Syndrome (A severe hypersensitive reaction affecting the skin and the mucous membranes)
ACE inhibitors Angioedema (allergic skin reaction characterized by patches of well defined swelling)

Table 4: Host Factors known to predispose to adverse drug reactions

Factor At Risk Group Drug(s)
Age Older Many
Sex Female Many
HLA HLA-DQw2 Aspirin
  HLA-B7,D22,D23 Insulin
  HLA-B*5701 Abacavir
  HLA-B*1502 Carbamazepine
  HLA-B*5802 Allopurinol
  HLA-DR9 Penicillin
Infection HIV Cotrimoxazole
  EBV Ampicillin

Table 5: Cutaneous Reactions to Drugs

Manifestation Examples
Rash like eruption originating on the trunk Antibiotics, anticonvulsants
Urticaria (A condition in the skin characterised by reddened irregular, elevated patches and severe itching, usually due to an allergic reaction) Most drugs
Purpura- vasculitis (Bleeding under the skin, causing red/purple discolourations) Allopurinol
Photodermatitis (Inflammation of the skin, caused by exposure to UV light). Griseofulvin, sulphonamides
Steven Johnson Syndrome Allopurinol, sulphonamides, anticonvulsants
Contact dermatitis (Inflammation of the skin) Antibiotics

Table 6: Clinical Manifestations of Immune Mediated Drug Hypersensitivity

Manifestation Clinical Features
Anaphylaxis (Severe allergic reaction) Urticaria or angioedema (as described above), irritation / inflammation of the nose, asthma, abdominal pain
Pulmonary (Lung) Asthma, Inflammation of lung tissue
Cardiac (Heart) Inflammation of the heart muscle
Hepatic (Liver) Hepatitis (inflammation of the liver)
Haematological (Blood) Deficiencies of red blood cells, platelets, white blood cells (eg neutrophils)
Renal (Kidney) Inflammation of the kidney

(Article kindly contributed by Assoc Prof. John W Quin, MBBS (hons) BSc (hons) PhD FRACP FRCPA, Director Clinical Immunology Sydney South West Area Health Services Assoc Professor Medicine UNSW, Editorial Advisory Board member of the Virtual Allergy Centre: and Dr Gary A Unglick MBBS (hons) Advanced Trainee Registrar Clinical Immunology Sydney South West Area Health Services.)

References

  1. Vervloet D, Durham S. Adverse reactions to drugs. BMJ 1998; 316: 1511-1514.
  2. Huic M, Mucolic V, Vrhovac B, Francetic I, Bakran I, Giljanovic S. Adverse drug reactions resulting in hospital admission. Int J Clin Pharmacol Ther 1994; 32 (12): 675-682.
  3. Davies EC, Green CF, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital inpatients: a pilot study. J Clin Pharm Ther 2006; 31(4): 335-341.
  4. Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC, Cadoret C, Fish LS, Garber L, Kelleher M, Bates DW. Incidence and preventability of adverse events among older persons in the ambulatory setting JAMA 2003; 289(9): 1107-1116.
  5. Rodriguez Velasco JG, Torres Valdos JE, Montero Mora P, Juarez Morales DT, Rodriguez E, Almeida Arvizu VM. Reactions to drugs: a review of literature. Rev Alerg Mex 2006 ; 53(2) : 73-75.
  6. Coopman SE, Johnson RA, Platt R, Stern RS. Cutaneous diseases and drug reactions in HIV infection. N Engl J Med 1993; 328 (23): 1670-1674.
  7. Riedl MA, Casillas MD. Adverse drug reactions: types and treatment options. Am Fam Physician 2003; 68: 1781-1790.
  8. Naisbitt DJ, Williams DP, Pirmohamed M, Kitteringham NR, Park BK. Reactive metabolites and their role in drug reactions. Curr Opin Allergy Clin Immunol 2001; 1:317-325.
  9. Pichler WJ. Pharamacological interaction of drugs with antigen-specific immune receptors: the p-I concept. Curr Opin Allergy Clin Immunol 2002; 2:301-305.
  10. Matzinger P. An innate sense of danger Semin immunol 1998; 10:399-415.
  11. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, castley A, Mamotte C, Maxwell D, James I, Christiansen FT. Association between presence of HLA-B* 5701, HLA-DR7, and HLA-DQ3 and hypersensitivity tom HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359(9308): 727-732.
  12. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, Hu SL, Wu MT, Chen GS, Wong TW, Hsiao PF, Chen WH, Shih HY, Fang WH, Wei CY, Lou YH, Huang YL, Lin JJ, Chen YT. Genetic susceptibility to carbamezepine-induced cutaneous drug reactions. Pharmacogenet Genomics 2006; 16(4): 297-306.
  13. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT. HLA_B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005; 102(17): 6237.
  14. Yang J, Qiao HL, Zhang YW, Jia LJ, tian X, Gao N. HLA-DRB genotype and specific IgE responses in patients with allergies to penicllins. Chin Med J (Engl) 2006; 119(6): 458-466.
  15. Carr A, Cooper DA. Pathogenesis and management of HIV-associated drug hypersensitivity. AIDS Clin Rev 1996; 96:65-97.
  16. Zanocchi M, Tibaldi V, Amati D, Fracisetti F, Martinelli E, Gonella M, Cerrato F, Ponte E, Luppino A, Bardelli B, Canade A, Gariglio F, Moiraghi C, Molaschi M. Adverse drug reactions as a cause of visits to emergency department: incidence, features and outcomes. Recenti Prog Med 2006; 97(7-8): 381-388.
  17. Nassar A-E F, Lopez-Anaya A. Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov & Devel 2004; 7(1): 126-136.
  18. Amacher DE. Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective. Curr Drug Metab 2006; 7(3):219-229.
  19. Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions . DDT 2003; 8(18): 832-837.
  20. Komericki P, Arab E, Grims R, kranke B, Aberer W. Tryptase as severity marker in drug provocation tests. Int Arch Allergy Immunol 2006; 140: 164-169.
  21. Kalogeromitros,Dimitrios; Rigopoulos,Dimitrios; Gregoriou,Stamatios; Papaioannou,Dimitrios; Mousatou,Vassiliki; Katsarou-Katsari,Alexandra. Penicillin hypersensitivity :value of clinical history and skin testing in daily practice. Allergy Asthma Proc. 2004 May-Jun;25(3):157-60.
  22. Stember, Rishon H. Prevalence of Skin Test Reactivity in Patients with Convincing, Vague, and Unacceptable Histories of Penicillin Allergy. Allergy and Asthma proceedings. 2005, January-February;(6):59-64.
  23. Macy E, Richter PK, Falkoff R Skin Testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenges in patients with negative skin test responses to penicillin reagents. J Allergy Clin Immunol 1997; 100: 586-591
  24. Idsoe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ. 1968;38(2):159-188.
  25. Andrew P C McLean-Tooke, Claire A Bethune, Ann C Fay, Gavin P Spickett Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-1335.