Pharmacokinetic Principles

Key Points

First-order elimination describes a process in which the rate of drug elimination is directly proportional to the drug’s plasma concentration; most anesthetic and therapeutic drugs follow this model under normal physiological conditions.
Second-order elimination refers to nonlinear, capacity-limited kinetics in which the elimination rate depends on interactions between two reactants, typically a drug molecule and a saturable enzyme.
Zero-order elimination represents a constant, concentration-independent rate of elimination that occurs when metabolic pathways are saturated.

First-Order Elimination

First-order elimination is the most common kinetic pattern observed for most clinically administered drugs and represents the most intuitive pharmacokinetic behavior. It is characterized by a constant fraction of the drug cleared per unit time, resulting in a predictable and reproducible decline in plasma concentration.^1,2 As a result, the rate of drug elimination is directly proportional to the plasma concentration; at higher concentrations, the body eliminates more drug per unit time, and at a lower concentration, elimination slows proportionally.^1,3 Clearance remains stable across therapeutic levels, allowing for an exponential decline in plasma drug concentration.^1,2
In first-order kinetics, the half-life remains constant, regardless of the administered dose.¹ Plasma concentration declines exponentially, producing the classic semilogarithmic decay on a linear scale concentration-versus-time graphs (Figure 1).^1,3 Dose adjustments are predictable; doubling the dose leads to a proportional doubling of the plasma concentration.¹
Most clinically relevant medications, including most anesthetic agents, follow first-order elimination under standard physiologic conditions.^3,4 The predictable elimination profile supports the use of standardized dosing regimens and simplifies therapeutic monitoring.¹
Drugs commonly demonstrating first-order kinetics:^1,3,4
- Analgesics: acetaminophen, opioids (morphine, hydromorphone, fentanyl)
- Local anesthetics: lidocaine, bupivacaine, ropivacaine
- Volatile anesthetics: sevoflurane, desflurane, isoflurane
- Intravenous anesthetics: propofol (at therapeutic concentrations), ketamine, etomidate, benzodiazepines
- Neuromuscular blocking agents: rocuronium, vecuronium
- Antibiotics: penicillins, cephalosporins, fluoroquinolones
The predictable concentration-time curve associated with first-order elimination makes dosing straightforward. The time to steady state under first-order kinetics is also highly predictable. After reaching a constant infusion rate, plasma concentrations approach a steady state, generally after approximately 5 half-lives, with about 97% of the final steady-state concentration reached by this point.^1,2
Drug accumulation being proportional to dose permits reliable titration and minimizes unexpected accumulation.1 Toxicity risk increases proportionally with dose escalation, aligning with the linear nature of these kinetics. This allows for safe titration, even with drugs with a narrow therapeutic index, provided the clinician understands the drug’s half-life and clearance characteristics.
Drug interactions that increase clearance will reduce concentrations proportionally. Renal or hepatic impairment may shift kinetics away from first order, but often predictably.⁴ Most therapeutic drug monitoring models assume first-order behavior.¹
Overall, first-order kinetics offer clinicians a reliable framework for dosing, monitoring, and adjusting most medications used in anesthesia.^1,3,4

Figure 1. First-order elimination

Second-Order Elimination

Second-order elimination, also known as Michaelis-Menten kinetics, is uncommon in clinical pharmacology and is typically discussed as a theoretical model rather than a routine clinical phenomenon.⁵ In second-order kinetics, the rate of elimination depends on the interaction between two reactants.
This phenomenon often reflects underlying molecular events such as:⁵
- Drug-enzyme interactions
- Drug-protein binding
- Reactions involving two drug molecules
- Enzyme saturation dynamics in multistep metabolic pathways
In second-order kinetics the elimination rate is proportional to the square of the drug concentration, reflecting that elimination becomes more dependent on molecular collisions or saturable binding interactions.⁵ Clearance is not constant but instead varies depending on the concentration and the availability of binding partners or enzymes, so clearance decreases as concentrations rise.⁵ Half-life increases at higher concentrations because elimination slows as enzymes or binding molecules become saturated, resulting in nonlinear and less predictable drug behavior. The concentration-versus-time relationship is often curvilinear when plotted on standard axes (as seen in Figure 2).³
These systems exhibit unpredictable behavior as concentration increases. When enzymatic pathways reach saturation, the system may shift toward zero-order elimination.⁵ On the other hand, at low drug concentrations, where enzyme capacity exceeds drug availability, the system may revert to first-order kinetics.⁵
Although rare, some drugs may exhibit second-order behavior under extreme conditions. For example, propofol can demonstrate second-order elimination at unusually high infusion rates where enzyme-drug interactions become limiting.⁵ Clinically, these nonlinear reactions are most relevant when evaluating the pharmacokinetics of drug overdose, experimental drug systems, or medications administered at supratherapeutic infusion rates.
Due to second-order elimination, which results in concentration-dependent clearance, dosing becomes less predictable as concentration increases.⁵ This complicates dosing because small increases in dose may cause disproportionate increases in plasma levels. This can lead to:
- Unexpected drug accumulation
- Rapid shifts into toxic concentration ranges
- Increased risk of adverse effects once enzymatic capacity is overwhelmed
Therefore, when second-order behavior is suspected, close monitoring and cautious dose adjustments are essential.⁵

Figure 2. Second-order elimination

Zero-Order Elimination

Zero-order elimination describes a kinetic pattern in which a constant amount of drug is eliminated per unit time, regardless of the plasma drug concentration.^1,3 Unlike first-order kinetics, the rate of elimination does not increase in the presence of high drug levels because the metabolic pathway responsible for drug removal is functioning at maximum capacity. This occurs when the metabolic or elimination pathways, typically hepatic enzymes with limited turnover rates or renal secretory pathways with finite transport capacity, become fully saturated.^1,2
In zero-order kinetics, clearance is fixed and no longer proportional to drug concentration. Unlike in first-order kinetics, the half-life is not constant and tends to decrease as the concentration decreases.^1,2 Plasma concentration decreases linearly over time rather than exponentially (Figure 3).³ Zero-order elimination often occurs only when drug concentrations are sufficiently high to overwhelm the body’s ability to process them. Once concentrations fall below saturation thresholds, elimination frequently reverts to first-order kinetics.
Zero-order kinetics are not commonly seen in anesthetic medications but are clinically observed with the following medications:^1,3,4
- Ethanol (due to saturation of alcohol dehydrogenase)
- Phenytoin (near therapeutic levels)
- Aspirin (at high anti-inflammatory doses, not analgesic doses)
- Theophylline and warfarin overdose
Because the elimination rate is fixed, dosing under zero-order kinetics can be challenging. Steady state concentrations are difficult to predict, necessitating frequent therapeutic monitoring. Even small increases in dose may cause large, unpredictable increases in plasma concentration, necessitating cautious dose titration.^1,3,4 The risk of toxicity is high, particularly when metabolic pathways are already operating at saturation.
Understanding the principles of zero-order elimination is critical when managing medications with narrow therapeutic indexes or in overdose situations.^1,2

Figure 3. Zero-order elimination

References

Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 5th ed. Philadelphia, PA; Wolters Kluwer; 2019: 45-78.
Gibaldi M, Perrier D. One-Compartment Model. In: Pharmacokinetics. 2nd ed. New York, NY; Marcel Dekker; 2007: 1-35
Yartsev A. First-order, zero-order and non-linear elimination kinetics. Deranged Physiology. Updated 18 Dec 2023. Accessed November 22, 2025. Link
Borowy CS, Ashurst JV. Physiology, zero and first order kinetics. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Link
Gibaldi M, Perrier D. Nonlinear pharmacokinetics. In: Pharmacokinetics. 2nd ed. New York, NY; Marcel Dekker; 2007: 271-312.

Other References

Ninja Nerd Video: Pharmacokinetics: Drug Clearance. Accessed December 8th, 2025. Link

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