Most medications are not given as a single dose. They are administered repeatedly at fixed intervals to maintain consistent therapeutic levels. This is known as a multiple dosage regimen. Understanding this concept helps pharmacists design dosing schedules that ensure safety, avoid toxicity, and maintain drug concentration within the therapeutic window.
What Are Multiple Dosage Regimens?
A multiple dosage regimen refers to the administration of repeated doses of a drug at regular time intervals. Examples include taking tablets twice daily, IV injections every 8 hours, or daily insulin doses. The goal is to maintain effective plasma levels over time.
Key Concepts in Multiple Dosing
1. Drug Accumulation
With each dose, some of the drug remains in the body from the previous dose. As doses continue, the drug accumulates until elimination balances input.
Accumulation depends mainly on:
- Drug half-life
- Dosing interval (τ)
2. Steady State Concentration (Css)
Steady state occurs when the rate of drug administration = rate of elimination.
It takes about 4–5 half-lives to reach steady state, regardless of dose size.
3. Peak and Trough Levels
- Peak concentration: highest level after a dose
- Trough concentration: lowest level before the next dose
These values help evaluate therapeutic effectiveness and prevent toxicity.
4. Fluctuation
Fluctuation refers to the difference between peak and trough concentrations. It depends on:
- Half-life
- Dosing interval
Short dosing intervals reduce fluctuation; long intervals increase it.
Factors Affecting Multiple Dosing
1. Half-Life
- Long half-life → less fluctuation, slower steady state
- Short half-life → more fluctuation, faster steady state
2. Dosing Interval (τ)
- Shorter intervals → higher accumulation, less fluctuation
- Longer intervals → lower accumulation, more fluctuation
3. Dose Size
Higher doses lead to higher peak and trough concentrations.
Mathematical Expressions
1. Accumulation Factor (R)
R = 1 / (1 − e−kτ)
2. Steady-State Concentration
Css,max = (Dose / Vd) · R
Css,min = Css,max · e−kτ
Loading Dose in Multiple Dosing
A loading dose is used when the drug has a long half-life and waiting 4–5 half-lives to reach steady state is not practical.
Loading Dose = Ctarget × Vd
Maintenance doses then keep the drug level within the therapeutic range.
Therapeutic Drug Monitoring (TDM)
For drugs with narrow therapeutic indexes (e.g., digoxin, phenytoin, aminoglycosides), plasma levels must be monitored to adjust peak and trough concentrations.
Clinical Applications
1. Antibiotic Dosing
Multiple dosing helps maintain effective levels to kill bacteria without causing toxicity.
2. Chronic Conditions
Conditions like hypertension, diabetes, epilepsy, and heart failure require long-term multiple dosing.
3. Adjusting Doses in Renal and Hepatic Impairment
Impaired elimination prolongs half-life, increasing accumulation and toxicity risk.
4. Preventing Drug Accumulation Toxicity
Understanding multiple dosing prevents dangerously high levels in drugs with slow elimination.
Advantages of Multiple Dosage Regimens
- Maintains consistent therapeutic levels
- Reduces risk of subtherapeutic exposure
- Allows flexible dose adjustments
- Helps personalize treatment
Limitations
- Risk of drug accumulation
- Requires patient compliance
- More complex calculation in drugs with non-linear kinetics
Detailed Notes:
For PDF style full-color notes, open the complete study material below:
PATH: PHARMD/ PHARMD NOTES/ PHARMD FOURTH YEAR NOTES/ BIOPHARMACEUTICS AND PHARMACOKINETICS/ MULTIPLE DOSAGE REGIMENS.
