Loading Dose


Definition/Introduction

In the field of medicine, the treatment for most conditions uses various pharmacological medications. For each of these individual medications, the route of administration, appropriate dosage, and frequency of use are determined by the medication’s pharmacokinetics (PK). PK is the relationship between an administered dose of a drug and its measured concentration within the body. An individual medication’s PK is governed by how it moves within the body through absorption, bioavailability, distribution, metabolism, and excretion.

The characteristics that define an individual medication’s PK can help determine the loading dose. While a patient is taking a specific drug to achieve the therapeutic benefit, the drug must reach a certain steady-state concentration.[1] Typically, for any medication, five to seven half-lives are required for this to be achieved. Reaching this concentration is typically not an issue for drugs with short half-lives; however, other medications or conditions may require more rapid therapeutic onset. For instances where a therapeutic steady-state concentration is needed immediately, loading doses can be utilized to more rapidly achieve this therapeutic concentration.[1]

A loading dose is typically calculated through the following formula:

LD=(Volume of Distribution X Concentration Steady State)/Bioavailability

For this formula, concentration steady-state is defined as the therapeutic concentration of medication in the body, while bioavailability is the fraction of an administered dose that reaches systemic circulation. The volume of distribution is typically calculated as follows:

Vd=Dose of medication given/Concentration in the Plasma

The calculation of loading dose should not be confused with maintenance dose, which is the dose required to maintain steady-state concentration. This calculation is: 

MD=(Concentration Steady State X Clearance X Dosing Interval)/Bioavailability

Clearance can be determined using the known half-life of a medication, which is the length of time required for a dose to reach 50% of its initial plasma concentration. Clearance can ultimately be determined through: 

CL=(0.693 X Vd)/ Half-life

Issues of Concern

When prescribing a loading dose of a new medication, there are many factors that a clinician has to consider. Through the formulas above, the loading dose of any drug is influenced by many of the PK variables.

Bioavailability is typically affected by the route of administration of the medication. Each medication typically has a route that provides the best bioavailability. For example, in one study, researchers found that sublingual administration of misoprostol had significantly higher bioavailability compared to oral administration.[2] Higher bioavailability allows for the utilization of a lower loading dose to reach the same steady-state concentration, leading to better medication safety and efficacy. Patient comorbidities can also affect medication bioavailability. For example, celiac disease causes atrophy of the duodenal villi, which can hinder the absorption and bioavailability of medications given orally. As a result, other drugs have been developed to allow proper treatment for these patients, such as a medication to increase absorption of iron in patients with celiac disease and iron deficiency anemia.[3]

Besides, various physiological factors can affect the concentration and pharmacokinetics of medication. One study found that the clearance of ciprofloxacin significantly decreases with age and worsening kidney function.[4] Failure to adjust for these factors could lead to toxicity or other related side effects. Ultimately, it is essential to consider all factors while dosing medications, as any change in these variables, will inevitably affect the loading dose and consequently, steady-state concentration.

Clinical Significance

A medication’s loading dose has many vital clinical applications. In emergency circumstances, drugs need to reach therapeutic concentration rapidly, often requiring a loading dose. For example, studies have found that a loading dose of levetiracetam is essential for adequate treatment of status epilepticus.[5] Also, knowledge of factors that may affect a medication’s loading dose is imperative to pharmacological treatments for chronic conditions. For example, initiation of dofetilide for treatment of atrial fibrillation requires an initial loading dose before reaching therapeutic concentrations. As a clinician administers this medication, they must monitor creatinine clearance and QTc interval length and adjust the dosage accordingly to avoid potentially deadly side effects such as ventricular tachycardia.[6]

Nursing, Allied Health, and Interprofessional Team Interventions

Using pharmacological therapy to treat a patients underlying condition is common in today's medical field. Although these therapies can be beneficial, they can also cause significant harm to the patient. One study found that almost 11% of prescriptions have errors, and 16% of these errors result in harm towards the patient.[7] This situation makes it essential that dosing medications are done with an interdisciplinary team to ensure efficacy and safety. Ways to help facilitate this would be by:

  • Having an open line of communication between all clinicians and specialties
  • Ensure clinicians and pharmacists work together to ensure proper dosing and medication choice
  • Order drug blood concentrations when available.
  • Educate family and patient about potential adverse drug reactions
  • Ensure appropriate specialties are involved with the care of a patient when deemed appropriate

Interdisciplinary efforts become even more essential when a situation with a patient becomes more critically ill, requiring higher levels of care. By working in an interdisciplinary team, patient outcomes can potentially improve, and medication errors avoided.[8] [Level IV]


Article Details

Article Author

Anthony Miniaci

Article Editor:

Vikas Gupta

Updated:

8/23/2021 7:29:22 AM

PubMed Link:

Loading Dose

References

[1]

Fan J,de Lannoy IA, Pharmacokinetics. Biochemical pharmacology. 2014 Jan 1;     [PubMed PMID: 24055064]

[2]

Amini M,Reis M,Wide-Swensson D, A Relative Bioavailability Study of Two Misoprostol Formulations Following a Single Oral or Sublingual Administration. Frontiers in pharmacology. 2020;     [PubMed PMID: 32116725]

[3]

Giancotti L,Talarico V,Mazza GA,Marrazzo S,Gangemi P,Miniero R,Bertini M, Feralgineā„¢ a New Approach for Iron Deficiency Anemia in Celiac Patients. Nutrients. 2019 Apr 20;     [PubMed PMID: 31009990]

[4]

Gai X,Shen N,He B,Zhou Q,Bo S,Li X,Zhai S,Yin A,Lu W, [Population pharmacokinetics of ciprofloxacin in Chinese elderly patients with lower respiratory tract infection]. Zhonghua yi xue za zhi. 2015 May 26;     [PubMed PMID: 26463606]

[5]

Rösche J,Dudek M,Teleki A,Godau J,Bösel J, [Levetiracetam for treatment of status epilepticus - an update]. Fortschritte der Neurologie-Psychiatrie. 2019 Jun;     [PubMed PMID: 31261415]

[6]

Torp-Pedersen C,Brendorp B,Køber L, Dofetilide: a class III anti-arrhythmic drug for the treatment of atrial fibrillation. Expert opinion on investigational drugs. 2000 Nov;     [PubMed PMID: 11060831]

[7]

Fitzgerald RJ, Medication errors: the importance of an accurate drug history. British journal of clinical pharmacology. 2009 Jun;     [PubMed PMID: 19594536]

[8]

Bakker T,Klopotowska JE,de Keizer NF,van Marum R,van der Sijs H,de Lange DW,de Jonge E,Abu-Hanna A,Dongelmans DA, Improving medication safety in the Intensive Care by identifying relevant drug-drug interactions - Results of a multicenter Delphi study. Journal of critical care. 2020 Feb 21;     [PubMed PMID: 32145656]