Education And Debate
Joining the DoTS: new approach to classifying adverse drug reactionsBMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7425.1222 (Published 20 November 2003) Cite this as: BMJ 2003;327:1222
Authors Dose related classification Time related classification Haber 1924w1 Haber’s Law: the severity of a reaction is a function of concentration and the duration of exposure Wayne 1958w2 Distinguishes predictable and unpredictable effects Lasagna 1964w3 Distinguishes predictable and unpredictable effects Levine 1973w4 Distinguishes dose related and non-dose related reactions Distinguishes acute, subacute, and chronic toxic reactions Wade and Beeley 1976w5 Distinguishes dose related and non-dose related effects Distinguish long term and teratogenic effects Rawlins and Thompson,1977 w6 Propose two types of adverse drug reaction: A and B (see text) Grahame-Smith and Aronson 1984w7 Classify types A and B as dose related and non-dose related reactions Add two time related categories: long term and delayed Hoigné et al 1990w8 Distinguish acute, subacute, and latent allergic reactions Park et al., 1992w9 Label Grahame-Smith and Aronson’s categories types C (long term) and D (delayed) Laurence and Bennett 1992w10 Split type C into two types, type C (continuous) and type E (end of use) Ferner and Mann, 1997w11 Distinguish five patterns of time course Aronson and Ferner 2003 (this paper) Distinguish three types of dose related adverse reactions: toxic effects, collateral effects, hypersusceptibility Distinguish time dependent and time independent reactions
Table B Time related classification of adverse drug reactions
Type of reaction Examples Implications Time independent Due to change in dose or concentration (pharmaceutical effects) Toxicity due to increased systemic availability Beware of changing formulations of some drugs (eg modified-release formulations of lithium) Due to change in dose or concentration (pharmacokinetic effects) Digitalis toxicity due to renal insufficiency Forewarn the patient; monitor carefully throughout treatment; alter dosage when pharmacokinetics change (eg renal insufficiency); avoid interacting drugs Occurs without change in dose (pharmacodynamic effects) Digitalis toxicity due to hypokalaemia Forewarn patient; monitor carefully throughout treatment; avoid precipitating (pharmacodynamic) factors; avoid interacting drugs Time dependent Rapid (due to rapid administration) Red man syndrome (vancomycin) Administer slowly Hypertension (digitalis) Hypotension (iodipamide) First dose [of a course] Hypotension (α1 adrenoceptor antagonists and angiotensin converting enzyme inhibitors) Take special precautions for the first dose Type I hypersensitivity reactions Careful history taking; if a reaction occurs, avoid re-exposure; counsel the patient Early (abates with repeated exposure) Adverse reactions that involve tolerance (eg nitrate induced headache) Monitor during early stages; give appropriate reassurance; expect adverse effects if strategies to avoid tolerance are adopted Intermediate (risk increases at first, then diminishes) Venous thromboembolism (antipsychotic drugs) Monitoring not needed after the high risk period unless susceptibility changes; withdraw drug if a reaction develops Hypersensitivity reactions types II, III, and IV Late (risk increases with time) Osteoporosis (corticosteroids) Assess baseline function; forewarn the patient; monitor periodically during prolonged treatment Tardive dyskinesia (dopamine receptor antagonists) Retinopathy (chloroquine) Tissue phospholipid deposition (amiodarone) Withdrawal syndromes: opiates, benzodiazepines, hypertension (clonidine and methyldopa), myocardial infarction (β blockers) Withdraw slowly; forewarn the patient; replace with longer acting drug if withdrawal is not possible Delayed Carcinogenesis (ciclosporin, diethylstilbestrol) Avoid or screen; counsel or forewarn the patient Teratogenesis (thalidomide)
- Haber F. Zur Geschichte des Gaskrieges. In: Fuenf Vortaege aus den Jahren 1920–1923. Berlin: Springer, 1924:76-94.
- Wayne EJ. Problems of toxicity in clinical medicine. In: Walpole AL, Spinks A, eds. The evaluation of drug toxicity. London: Churchill, 1958:1-11.
- Lasagna L. The diseases drugs cause. Perspect Biol Med1964;19:457-70.
- Levine RR. Factors modifying the effects of drugs in individuals. In: Pharmacology. Drug actions and reactions. Boston: Little, Brown, 1973:261-91.
- Wade OL, Beeley L. Adverse reactions to drugs. 2nd ed. London: William Heinemann, 1976.
- Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.
- Grahame-Smith DG, Aronson JK. Adverse drug reactions. In: Oxford textbook of clinical pharmacology and drug therapy. Oxford: Oxford University Press, 1984:132-57.
- Hoigné R, Jaeger MD, Wymann R, Egli A, Muller U, Hess T, et al. Time pattern of allergic reactions to drugs. Agents Actions Suppl 1990;29:39-58.
- Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34:377-95.
- Laurence DR, Bennett PN. Clinical pharmacology. Edinburgh: Churchill Livingstone 1992:121-2.
- Ferner R, Mann RD. Drug safety and pharmacovigilance. In: Page C, Curtis MJ, Sutter MC, Walker MJA, Hoffman BB, eds. Integrated pharmacology. 1st ed. London: Mosby, 1997:83-90.
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