Drug-related side effects and adverse reactions

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Revision as of 05:20, 23 November 2007 by imported>Robert Badgett (Created a section on mechanisms by importing content that I helped write at WP)
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Drug toxicity, also called adverse drug reaction or adverse drug event, is defined as "manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning..."[1]

Mechanisms

As research better explains the biochemistry of drug use, less ADRs are Type B and more are Type A. Common mechanisms are:

  • Abnormal pharmacokinetics due to
    • genetic factors
    • comorbid disease states
  • Synergistic effects between either
    • a drug and a disease
    • two drugs

Abnormal pharmacokinetics

Comorbid disease states

Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.[2]

Genetic factors

For more information, see: Pharmacogenetics and Pharmacogenomics.

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[3][4]

Phase I reactions

Inheriting abnormal alleles of cytochrome P450can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[5].[6]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[7]

Phase II reactions

Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[7][6]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[6]

Interactions with other drugs

For more information, see: Drug interaction.

The risk of drug interactions is increased with polypharmacy.

Protein binding

These interactions are usually transient and mild until a new steady state is achieved.[8][9] These are mainly for drugs without much first-pass liver metabolism. The principle plasma proteins for drug binding are:[10]

  1. albumin
  2. α1-acid glycoprotein
  3. lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.[10]

Cytochrome P450

Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.[11].

Synergistic effects

An example of synergism is two drugs that both prolong the QT interval.


References

  1. ↑ National Library of Medicine. Drug toxicity. Retrieved on 2007-11-23.
  2. ↑ Clinical Drug Use. Retrieved on 2007-09-18.
  3. ↑ Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA 286 (18): 2270–9. PMID 11710893. [e]
  4. ↑ Goldstein DB (2003). "Pharmacogenetics in the laboratory and the clinic". N. Engl. J. Med. 348 (6): 553–6. DOI:10.1056/NEJMe020173. PMID 12571264. Research Blogging.
  5. ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
  6. ↑ 6.0 6.1 6.2 Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  7. ↑ 7.0 7.1 Evans WE, McLeod HL (2003). "Pharmacogenomics--drug disposition, drug targets, and side effects". N. Engl. J. Med. 348 (6): 538–49. DOI:10.1056/NEJMra020526. PMID 12571262. Research Blogging.
  8. ↑ DeVane CL (2002). "Clinical significance of drug binding, protein binding, and binding displacement drug interactions". Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961. [e]
  9. ↑ Benet LZ, Hoener BA (2002). "Changes in plasma protein binding have little clinical relevance". Clin. Pharmacol. Ther. 71 (3): 115–21. DOI:10.1067/mcp.2002.121829. PMID 11907485. Research Blogging. OVID full text summary table at OVID
  10. ↑ 10.0 10.1 Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions". The Annals of pharmacotherapy 36 (10): 1642–4. PMID 12369572. [e]
  11. ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
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