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Thread: Pharmacological Classification of Adverse Drug Reactions

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    Default Pharmacological Classification of Adverse Drug Reactions

    The most commonly used pharmacological classification is the A/B classification, which is based primarily on the perceived reaction of the adverse effect of the drug to dose and mechanism.

    Type A and type B reactions were originally defined as follows: "Type A reactions are the result of an exaggerated, but otherwise normal, pharmacological action of a drug given in the usual therapeutic doses ... They are usually dose-dependent"; "Type B reactions are totally aberrant effects that are not to be expected from the known pharmacological actions of a drug when given in the usual therapeutic doses to a patient whose body handles the drug in the normal way."
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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    PharmD Year 1 TomHsiung's Avatar
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    Default Re: Pharmacological Classification of Adverse Drug Reactions

    But, there are difficulties with the A/B classification definition:

    1. Type A reactions are said to be “usually dose-dependent”, implying that some may not be. However, if type A reactions result from an exaggeration of the “normal” pharmacological action, they should depend on dose. In fact, all adverse reactions are dose-related (see §1.6.2).

    2. It is not clear what is meant by a “normal pharmacological action”; the term implies that there may be, under some circumstances, abnormal pharmacological actions. By “normal” may be meant the action that is usually associated with a therapeutic effect, but even that is problematic (see §1.6.2).

    3. It is possible for a type A reaction to result from a “normal” pharmacological action without its being “exaggerated”. For example, alpha-adrenoceptor antagonists produce their therapeutic effect in benign prostatic hyperplasia by a degree of antagonism that, in vascular smooth muscle, is sufficient to cause hypotension; yet hypotension induced by an alpha-blocker would presumably be classified as a type A reaction.

    4. The definition of type B reactions does not specify whether they are or are not dose- dependent. Indeed, although reactions under this heading are generally regarded as being non-dose-dependent [167], nothing about the definition quoted above restricts type B reac- tions in this way. For example, dose-dependent nausea and vomiting due to erythromycin could be classified as a type A reaction as defined, because it is dose-related, or as a type B reaction as defined, since its mechanism is neither known nor predictable from its antibacterial (i.e. “normal”) action. In other words, it is not clear whether erythromycin- induced nausea should be classified as Type A or Type B according to the definitions. This highlights another difficulty—that an adverse reaction that is at first classified as being of type B might have to be reclassified as being of type A when its pharmacological basis and dose-relation become known.

    5. Not all adverse reactions can be comfortably accommodated within this classification. For example, corticosteroid-induced osteoporosis depends not only on dose but also on duration of therapy, and tumours induced by chemotherapy with alkylating agents depend on dose but are greatly delayed. These distinctions have implications for drug develop- ment and the management (monitoring, prevention, diagnosis, and treatment) of adverse drug reactions.
    Last edited by TomHsiung; Fri 1st July '16 at 5:45pm.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

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    Default Re: Pharmacological Classification of Adverse Drug Reactions

    Dose-relatedness of adverse drug reactions

    It is a basic pharmacological principle that effects of drug involve interactions between chemical entities and are therefore subject to chemical laws, including the Law of Mass Action. This implies that all drug effects, beneficial or adverse, including immunological reactions, are concentration-related and therefore dose-related. Indeed, many well-known immunological reactions are demonstrably dose-related or concentration-related, including: hay fever in response to changing pollen counts; the immunogenic response to hepatitis B vaccine; desensitization by the use of increasing doses of antigen; type IV hypersensitivity skin reaction. For example, both the induction and subsequent amplification of skin hypersensitivity to dinitrochlorobenzene increase linearly with the logarithm of the sensitizing dose, as does the response to a subsequent challenge.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

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    Default Re: Pharmacological Classification of Adverse Drug Reactions

    EIDOS - A mechanistic classification of adverse drug reactions

    E = the Extrinsic chemical species that initiates the effect
    I = the Intrinsic chemical species that it affects
    D = the Distribution in the body of these species
    O = the (physiological or pathological) Outcome (the adverse effect)
    S = the Sequela (the adverse reaction)

    Pharmacological Classification of Adverse Drug Reactions-screen-shot-2016-07-01-at-8-53-09-pm-png
    Pharmacological Classification of Adverse Drug Reactions-screen-shot-2016-07-01-at-8-53-33-pm-png

    Figure 1.10 The question to be asked at each stage of the EIDOS classification process.

    Pharmacological Classification of Adverse Drug Reactions-screen-shot-2016-07-01-at-9-04-53-pm-png
    ======
    Extrinsic
    ======
    Adverse drug effects result from the introduction into the body of an extrinsic chemical species (E) in a medicinal product, or a species derived from it (E'), for example by metabolism. Different extrinsic species can be involved in adverse effects:
    • the drug molecule itself;
    • an excipient;
    • a contaminant;
    • an adulterant, such as lead or arsenic in herbal remedies, or over-sulfated chondroitin sulfate deliberately introduced into batches of heparin
    • a degradation product (before introduction into the body), such as the degradation products in out-dated tetracycline that have lead to renal tubular damage;
    • a derivative (E') of one of the above, particularly a metabolite of the parent compound.

    ======
    Intrinsic
    ======
    There are three types of interaction between an extrinsic chemical species and an intrinsic chemical species (a tissue or fluid in the body) that can result in an adverse effect:
    Molecular interactions Most interactions between the extrinsic species (E or E') and the intrinsic species (I) are molecular.
    Alterations in the extracellular environment Some adverse effects result from alterations in the composition of the extracellular fluid, for example by dilution, alteration of hydrogen ions, or alterations in the concentrations of solutes, such as sodium or potassium ions.
    Physical or physicochemical effects Adverse effects sometimes result from physical or physicochemical effects, such as direct tissue damage or precipitation of a drug (for example within the renal tubules, in the bile, or in the stomach)

    Molecular interactions
    The intrinsic molecules that can be involved in interactions with extrinsic molecules include:
    • nucleic acids - covalent adducts between cellular DNA and alkylating agents, such as melphalan, probably explain the increased risk of leukemia in patients treated with these drugs;
    • enzymes - most drug action involving enzymes is via enzyme inhibition; some drug interactions involve induction: 1).reversible effects - the peptidase that metabolizes angiotensin I to angiotensin II, angiotensin-converting enzyme (ACE), also metabolizes bradykinin; ACE inhibitors therefore inhibit the breakdown of bradykinin, whose increased concentration probably explain the adverse reaction of angio-oedema and cough; drugs that inhibit or induce enzymes related to drug metabolism are also associated with adverse effects through drug interactions, and these are included as susceptibility factors in the DoTS classification; 2).irreversible effects - inhibition of platelet cyclo-oxygenase by aspirin, with a consequent tendency to hemorrhage that persists for several days after the end of treatment, is irreversible;
    • receptors - pharmacological receptors (including neurotransmitter, hormone, and cytokine receptors) are the main targets for the actions of drugs; adverse effects can result from altered receptor action, in the target organ or elsewhere, either by a direct effect of the drug on the receptor (for example agonists and antagonists) or by indirect effects (for example neurotransmitter releasers or inhibitors of neurotransmitter reuptake or metabolism);
    • ion channels/transporters - inhibition of potassium channels in the distal convoluted tubule of the kidney by triamterene causes hyperkalemia; excess inhibition of the Na+/K+/2Cl- co-transporter by loop diuretics in the loop of Henle in the kidney causes hyponatremia and dehydration;
    • other proteins
      • immunological proteins - immunological effects of all the four types classified by Gell and Coombs can result from interactions between large extrinsic molecules (for example peptides and proteins) and intrinsic proteins or cells, from direct effects on components of the immune pathway, or by formation of immunogenic adducts, as exemplified by the haptens formed between the penicilloyl moiety of beta-lactam antibacterial agents and intrinsic proteins; such effects include the interaction between penicillins and IgE, causing anaphylaxis in sensitized individuals, or between proteins in horse serum and IgG, leading to serum sickness in those treated with horse-derived snake antivenoms;
      • tissue protein - direct damage to structural proteins can cause functional derangement, as happens when the metabolite N-acetyl-p-benzoquinone-imine (NAPQI) binds covalently to sulfhydryl-containing hepatic and renal proteins after parcetamol (acetaminophen) poisoning.

    Alteration of the extracellular environment
    The extracellular environment can change as a consequence of molecular interactions of the types mentioned above, as happens, for example, when chlorpropamide acts on vasopressin receptors. However, there can be direct or non-specific effects on the components of the extracellular environment. These can affect water, hydrogen ions (pH), and other ions.


    • water - crystalloids, such as 5% dextrose, can cause water intoxication directly; absorption of glycine solution during transurethral resection of the prostate gland can have important, albeit transient, effects on cardiovascular and neurological function;
    • pH - changes in hydrogen ion concentration can lead to important local or systemic adverse effects; large-volume infusions of solutions (such as sodium chloride 0.9%) that contain strong anions can cause metabolic acidosis;
    • other ions - high concentrations of cations, such as sodium, can result directly from the use of antibacterial drugs made up as salts, such as sodium ticarcillin.

    Physical or physicochemical interactions
    Examples of adverse reactions that result from physical or physiochemical effects include renal calculi due to precipitation of triamterene in the renal tract and gallstones due to precipitation of sulindac in the biliary tract. Corrosives, for example phenol used for nerve ablation, can cause non-specific tissue damage.
    ========
    Distribution
    ========
    The extrinsic (E or E') and intrinsic (I) species will interact only when they are both found in the same place. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse effects. For example, histamine H1 receptor antagonists (antihistamines), such as chlorphenamine, that cross the blood-brain barrier can act on CNS histamine receptors and cause drowsiness. Newer antihistamines, such as cetirizine, do not generally cross the blood-brain barrier in significant amounts and do not reach CNS H1 receptors; they therefore do not cause drowsiness.
    =======
    Outcome
    =======
    Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes. Examples of these are listed in Table 1.9, based on a published pathological classification. Some adverse effects arise through a combination of mechanisms.

    Pharmacological Classification of Adverse Drug Reactions-screen-shot-2016-07-02-at-8-50-56-pm-png

    =======
    Sequelae
    =======
    The sequelae of the pathological changes induced by a drug constitute the final step in the EIDOS classification and describe the clinically recognizable adverse drug reaction. There may be more than one sequela of an adverse drug effect.

    Sequelae can be classified using the DoTS system, thus producing a combined mechanistic and clinical pharmacological classification.
    Last edited by TomHsiung; Sat 2nd July '16 at 9:57pm.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

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