Dose (biochemistry)

A dose is a measured quantity of a medicine, nutrient, or pathogen which is delivered as a unit. The greater the quantity delivered, the larger the dose. Doses are most commonly measured for compounds in medicine. The term is usually applied to the quantity of a drug or other agent administered for therapeutic purposes, but may be used to describe any case where a substance is introduced to the body. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement. For bacterial or viral agents, dose typically refers to the amount of the pathogen required to infect a host. For information on dosage of toxic substances, see Toxicology. For information on excessive intake of pharmaceutical agents, see Drug overdose.

This article is about a measure of medication or chemical exposure. For other uses, see Dose (disambiguation).

In clinical pharmacology, dose refers to dosage or amount of dose administered to a person, whereas exposure means the time-dependent concentration (often in the circulatory blood or plasma) or concentration-derived parameters such as AUC (area under the concentration curve) and Cmax (peak level of the concentration curve) of the drug after its administration. This is in contrast to their interchangeable use in other fields.

Factors affecting dose

A 'dose' of any chemical or biological agent (active ingredient) has several factors which are critical to its effectiveness. The first is concentration, that is, how much of the agent is being administered to the body at once.

Another factor is the duration of exposure. Some drugs or supplements have a slow-release feature in which portions of the medication are metabolized at different times, which changes the impacts the active ingredients have on the body. Some substances are meant to be taken in small doses over large periods of time to maintain a constant level in the body, while others are meant to have a large impact once and be expelled from the body after its work is done. It's entirely dependent on the function of the drug or supplement.

The route of administration is important as well. Whether a drug is ingested orally, injected into a muscle or vein, absorbed through a mucous membrane, or any of the other types of administration routes, affects how quickly the substance will be metabolized by the body and thus effects the concentration of the active ingredient(s). Dose-response curves may illustrate the relationship of these metabolic effects.

Medicines

Over-the-counter medications

In over-the-counter medicines, dosage is based on age. Typically, different doses are recommended for children 6 years and under, children aged 6 to 12 years, and persons 12 years and older, but outside of those ranges the guidance is slim.[1] This can lead to serial under or overdosing, as smaller people take more than they should and larger people take less. Over-the-counter medications are typically accompanied by a set of instructions directing the patient to take a certain small dose, followed by another small dose if their symptoms don't subside. Under-dosing is a common problem in pharmacy, as predicting an average dose that is effective for all individuals is extremely challenging because body weight and size impacts how the dose acts within the body.[2]

Prescription drugs

Prescription drug dosage is based typically on body weight.[3] Drugs come with a recommended dose in milligrams or micrograms per kilogram of body weight, and that is used in conjunction with the patient's body weight to determine a safe dosage. In single dosage scenarios, the patient's body weight and the drug's recommended dose per kilogram are used to determine a safe one-time dose. In drugs where multiple doses of treatment are needed in a day, the physician must take into account information regarding the total amount of the drug which is safe to use in one day, and how that should be broken up into intervals for the most effective treatment for the patient.[4] Medication underdosing occurs commonly when physicians write prescriptions for a dosage that is correct for a certain time, but fails to increase the dosage as the patient needs (i.e. weight based dosing in children, or increasing dosages of chemotherapy drugs if a patient's condition worsens).[5]

Medical cannabis

Medical cannabis is used to treat the symptoms of a wide variety of diseases and conditions. The dose of cannabis depends on the individual, the condition being treated, and the ratio of cannabidiol (CBD) to tetrahydrocannabinol (THC) in the cannabis. CBD is a chemical component of cannabis that is not intoxicating and used to treat conditions like epilepsy and other neuropsychiatric disorders. THC is a chemical component of cannabis that is psychoactive. It has been used to treat nausea and discomfort in cancer patients receiving chemotherapy treatment. For anxiety, depression, and other mental health ailments, a CBD to THC ratio of 10 to 1 is recommended.[6] For cancer and neurological conditions, a CBD to THC ratio of 1 to 1 is recommended.[6] The correct dosage for a patient is dependent on their individual reaction to both chemicals, and therefore the dosing must be continually adjusted once treatment is initiated to find the right balance.

There is limited consensus throughout the scientific community regarding the effectiveness of medicinal cannabis.[7][8]

Cancer

Calculating drug dosages for treatment for more serious diseases like cancer is commonly done through measuring the patient's body surface area. There are approximately 25 different formulae for measuring a patient's body surface area, none of them exact.[9] Studies show that selecting the best method for an individual patient is a difficult task; consequently, patient often receive too much or too little medication due to their particular physical anomalies.[9] Therefore, these formulas are typically adjusted by what is known as 'toxicity-adjusting dosing,' whereby physicians monitor immune suppression and adjust dosing accordingly.[10] Because this strategy of trial and error requires close monitoring, it is inefficient, risky, and cost ineffective. Research into the development of safer and more accurate dosing methods is ongoing.

Ongoing research

Another approach that's been investigated recently is dosing on a molecular level, either through conventional delivery systems, nanoparticle delivery, light-triggered delivery, or other less known/used methods. By combining these drugs with a system that detects the concentration of drug particles in the blood, proper dosing could be achieved for each individual patient. Research in this field was initiated with monitoring of small-molecule cocaine levels in undiluted blood serum with electrochemical aptamer-based sensing. DNA aptamers, which are peptides that have with specific target molecules that they search for, fold in response to the molecule when they find it, and this technology was used in a microfluidic detection system to create an electrochemical signal that physicians can read. Researchers tested it on cocaine detection and found that it successfully found trace amounts of cocaine in blood.[11]

This research was expanded upon and led to the creation of a product called MEDIC (microfluidic electrochemical detector for in vivo continuous monitoring) developed by faculty at the University of California at Santa Barbara. MEDIC is an instrument that can continuously determine the concentrations of different molecules in the blood.[12] The blood doesn't have to be mixed with anything prior to testing to create a 'serum' as the first device did. MEDIC can detect a wide variety of drug molecules and biomarkers. In trials, early models of the device failed after about half an hour because the proteins in whole blood clung to the sensors and clogged the components. This problem was solved via a second chamber that allowed a liquid buffer to flow over the sensors with the blood, without mixing or disturbing the blood, so the results remained unchanged. The device is still in clinical trials and actual implementation in medicine is likely years away, however in the interim, its creators estimate that it could also be used in the pharmaceutical industry to allow for better testing in Phase 3 clinical trials.[13]

Vaccines

Vaccinations are typically administered as liquids and dosed in milliliters. Each individual vaccine comes with constraints regarding at what age they should be administered, how many doses must be given, and over what period of time. There are 15 vaccines that the Centers for Disease Control and Prevention recommend every person (in the United States and Canada) receive between birth and 18 years of age to protect against various infectious agents that may affect long-term health.[14] Most vaccines require multiple doses for full immunity, given in recommended intervals depending on the vaccine. There are several typical vaccination routes:[15]

  • Intramuscular: the needle is inserted perpendicular to the skin into the muscle, beneath the skin and (subcutaneous) tissues that rest on top.
  • Subcutaneous: the needle is inserted at a 45-degree angle into the (subcutaneous) tissue between the outer layer of the skin and the muscle.
  • Intranasal: the vaccine is sprayed into the nose and absorbed through the nasal passage.
  • Oral: the vaccine is swallowed and ingested.

Nutrition

For healthy humans, experts recommend daily intake quantities of certain vitamins and minerals. The Food and Nutrition Board, Institute of Medicine, and National Academy of Sciences sets a recommended Dietary Reference Intake (DRI) in several forms:[16]

  1. Recommended Dietary Allowance (RDA): average daily intake which adequately meets the nutrient requirements of 97-98% of healthy individuals.
  2. Adequate Intake (AI): established when the evidence gathered for an RDA is inconclusive, An AI is assumed to recommend a daily amount to meet nutritional adequacy.
  3. Tolerable Upper Intake Level (UL): maximum amount of a nutrient which can be consumed without causing adverse impacts to an individual's health.

DRIs are established for elements, vitamins, and macronutrients. Common elemental[17] and vitamin[18] dosages are milligrams per day (mg/d) or micrograms per day (μg/d). Common macronutrient[19] dosages are in grams per day (g/d). Dosages for all three are established by both gender and age.

Individuals take vitamin and mineral supplements to promote healthier lifestyles and prevent development of chronic diseases. There is no conclusive evidence linking continued vitamin and mineral supplement intake with longevity of life.[20]

Infectious dose

The infectious dose of a pathogen is the number of cells required to infect the host. All pathogens have an infectious dose typically given in number of cells. The infectious dose varies by organism and can be dependent on the specific type of strain.[21] Some pathogens can infect a host with only a few cells, while others require millions or billions.

Examples of infectious doses, ranked loosely in increasing order:[22]

Typically, stomach acids can kill bacteria below the infectious dosing range for a given pathogen and keep the host from feeling symptoms or falling ill. Complexes constructed by fat can protect infectious agents from stomach acid, making fatty foods more likely to contain pathogens that successfully infect the host. For individuals with low or reduced stomach acid concentrations, in infectious dosage for a pathogen will be lower than normal.[22]

Rather than being administered by a physician or individual, infectious dosages are transmitted to a person from other persons or the environment, are generally accidental, and result in adverse side effects until the pathogen is defeated by the individual's immune system or flushed out of the individual's system by excretory processes.

References
  1. Research, Center for Drug Evaluation and. "How Drugs are Developed and Approved - OTC (Nonprescription) Drugs". www.fda.gov. Retrieved 2017-04-08.
  2. Knopf, Hildtraud; Wolf, Ingrid-Katharina; Sarganas, Giselle; Zhuang, Wanli; Rascher, Wolfgang; Neubert, Antje (2013-01-01). "Off-label medicine use in children and adolescents: results of a population-based study in Germany". BMC Public Health. 13: 631. doi:10.1186/1471-2458-13-631. ISSN 1471-2458. PMC 3706213. PMID 23822744.
  3. http://www.lahc.edu/classes/nursing/nurs302/chapter14.pdf
  4. Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan (2016-04-12). "Weight-based dosing in medication use: what should we know?". Patient Preference and Adherence. 10: 549–560. doi:10.2147/PPA.S103156. ISSN 1177-889X. PMC 4835122. PMID 27110105.
  5. "Research paper insights: Medication underdosing and underprescribing: Issues that may contribute to polypharmacy, poor outcomes". ResearchGate. Retrieved 2017-04-07.
  6. "Archived copy" (PDF). Archived from the original (PDF) on 2017-04-10. Retrieved 2017-04-09.{{cite web}}: CS1 maint: archived copy as title (link)
  7. "How Effective Is Medical Marijuana? Here's A Closer Look At 14 Different Uses". Prevention. 2015-04-22. Retrieved 2017-04-09.
  8. Jacobson, Roni (2014). "The Case for Medical Marijuana". Scientific American Mind. 25 (3): 15. doi:10.1038/scientificamericanmind0514-15.
  9. Redlarski, Grzegorz; Palkowski, Aleksander; Krawczuk, Marek (2016-06-21). "Body surface area formulae: an alarming ambiguity". Scientific Reports. 6: 27966. Bibcode:2016NatSR...627966R. doi:10.1038/srep27966. ISSN 2045-2322. PMC 4914842. PMID 27323883.
  10. Gurney, H (2002-04-22). "How to calculate the dose of chemotherapy". British Journal of Cancer. 86 (8): 1297–1302. doi:10.1038/sj.bjc.6600139. ISSN 0007-0920. PMC 2375356. PMID 11953888.
  11. Swensen, James S.; Xiao, Yi; Ferguson, Brian S.; Lubin, Arica A.; Lai, Rebecca Y.; Heeger, Alan J.; Plaxco, Kevin W.; Soh, H. Tom. (2009-04-01). "Continuous, Real-Time Monitoring of Cocaine in Undiluted Blood Serum via a Microfluidic, Electrochemical Aptamer-Based Sensor". Journal of the American Chemical Society. 131 (12): 4262–4266. doi:10.1021/ja806531z. ISSN 0002-7863. PMC 2715559. PMID 19271708.
  12. Ferguson, Brian Scott; Hoggarth, David A.; Maliniak, Dan; Ploense, Kyle; White, Ryan J.; Woodward, Nick; Hsieh, Kuangwen; Bonham, Andrew J.; Eisenstein, Michael (2013-11-27). "Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals". Science Translational Medicine. 5 (213): 213ra165. doi:10.1126/scitranslmed.3007095. ISSN 1946-6234. PMC 4010950. PMID 24285484.
  13. "Device tests blood to watch drugs in real-time - Futurity". Futurity. 2014-01-22. Retrieved 2017-04-07.
  14. "Birth-18 Years Immunization Schedule - Shell | CDC". www.cdc.gov. Retrieved 2017-04-07.
  15. "Administering vaccines: Dose, route, site, and needle size" (PDF). Immunization Action Coalition, St. Paul, MN. 1 August 2019. Retrieved 13 April 2020.
  16. "Office of Dietary Supplements - Nutrient Recommendations : Dietary Reference Intakes (DRI)". ods.od.nih.gov. Retrieved 2017-04-07.
  17. Calcium, Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D. and; Ross, A. Catharine; Taylor, Christine L.; Yaktine, Ann L.; Valle, Heather B. Del (2011-01-01). "- Dietary Reference Intakes for Calcium and Vitamin D - NCBI Bookshelf". Retrieved 2017-04-07.
  18. Calcium, Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D. and; Ross, A. Catharine; Taylor, Christine L.; Yaktine, Ann L.; Valle, Heather B. Del (2011-01-01). "- Dietary Reference Intakes for Calcium and Vitamin D - NCBI Bookshelf". Retrieved 2017-04-07.
  19. Calcium, Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D. and; Ross, A. Catharine; Taylor, Christine L.; Yaktine, Ann L.; Valle, Heather B. Del (2011-01-01). "- Dietary Reference Intakes for Calcium and Vitamin D - NCBI Bookshelf". Retrieved 2017-04-07.
  20. "Office of Dietary Supplements - Multivitamin/mineral Supplements". ods.od.nih.gov. Retrieved 2017-04-07.
  21. Schmid-Hempel, Paul; Frank, Steven A (2017-04-07). "Pathogenesis, Virulence, and Infective Dose". PLOS Pathogens. 3 (10): 1372–3. doi:10.1371/journal.ppat.0030147. ISSN 1553-7366. PMC 2042013. PMID 17967057.
  22. https://www.fsis.usda.gov/shared/PDF/Atlanta2010/Slides_FSEC_JGreig_Doses.pdf?redirecthttp=true
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