What is the difference between half-life and duration of action of a medication?

Half-Life vs Duration of Action

Half-life and duration of action are distinct pharmacokinetic concepts: half-life is the time for plasma drug concentration to fall by 50%, while duration of action is the actual time a drug produces its clinical effect—these often do not correlate directly. 1, 2

Key Definitions

Half-Life

• Half-life (t½) represents the time required for the plasma or blood concentration of a drug to decrease by half, assuming first-order (linear) pharmacokinetics 1
• For drugs with biphasic elimination patterns (two-compartment models), the terminal half-life is clinically relevant—this reflects the gradual elimination phase after initial rapid distribution 1
• Half-life is calculated using the formula t₁/₂ = ln(2)/k, where k is the elimination rate constant 3

Duration of Action

• Duration of action is the actual time period during which a drug produces its therapeutic or clinical effect 2
• This depends on multiple factors beyond half-life: the absolute drug amount given, pharmaceutical preparation, reversibility of drug action, concentration-response curve slope, metabolite activity, and disease effects on elimination 2

Why They Don't Always Match

Factors Creating Discrepancy

Receptor binding and drug effect persistence can extend duration beyond what half-life predicts 2:

• A drug may continue producing effects even after plasma levels fall below certain thresholds
• Active metabolites can prolong duration independent of parent drug half-life 1

Site of action concentration matters more than plasma concentration 2:

• Tissue distribution and binding can maintain therapeutic effects despite declining plasma levels
• The concentration-response curve slope determines how much concentration must fall before effects diminish 2

Multiple effects of the same drug may have different durations 2:

• A single medication can have varying durations for different pharmacologic effects
• The duration depends on which specific effect is being measured 2

Clinical Implications

For Dosing Frequency

Drugs with short half-lives (< 12 hours) require more frequent dosing to maintain therapeutic levels and avoid excessive peak-to-trough fluctuations 1, 4:

• Examples include immediate-release metoprolol (t½ 3-4 hours) 5
• Short half-lives increase risk of withdrawal/discontinuation syndromes between doses 1, 6

Drugs with half-lives of 12-48 hours are ideal for once-daily dosing 4:

• This range optimizes patient compliance while maintaining stable drug exposure
• Avoids unnecessarily high peak concentrations 4

Drugs with very long half-lives (> 48 hours) allow extended dosing intervals 6:

• Examples include fluoxetine (t½ 4-6 days after chronic dosing, with norfluoxetine at 4-16 days) 7, 6
• Diazepam, aripiprazole, cariprazine, and penfluridol also have extended half-lives 6
• Some can be dosed weekly (e.g., fluoxetine weekly formulation) 7

For Time-Dependent vs Concentration-Dependent Killing

Time-dependent antibiotics (beta-lactams) require maintaining concentrations above the MIC for 40-50% of the dosing interval, making duration of action critical 8:

• The pharmacodynamic parameter T>MIC (time above MIC) determines efficacy 8
• Half-life helps predict how long therapeutic concentrations persist 8

Concentration-dependent antibiotics (fluoroquinolones) rely on peak concentration and AUC:MIC ratio rather than duration above MIC 8:

• These kill most efficiently at concentrations 10-12 fold above MIC 8
• Duration of action is less critical than achieving high peak levels 8

For Drug Discontinuation and Washout

Complete drug elimination requires 5-7 half-lives 9, 7:

• Fluoxetine with its long half-life persists for weeks after discontinuation, with active drug remaining 14-20 days or longer 7, 6
• This creates a prolonged "window" of subtherapeutic concentrations that may have clinical consequences 8, 9

Drugs with long half-lives have minimal withdrawal risk when discontinued 6:

• The gradual decline in plasma levels prevents abrupt discontinuation syndromes
• Conversely, short half-life drugs (e.g., immediate-release metoprolol) may cause rebound effects if abruptly stopped 1

For Steady-State Achievement

Time to steady state depends on half-life, not duration of action 7, 1:

• Steady state is reached after approximately 4-5 half-lives 7
• Fluoxetine takes 4-5 weeks to reach steady state due to its long half-life 7
• This delay in reaching steady state can complicate clinical trial design for drugs with very long half-lives 4

Special Populations Affecting Half-Life (Not Duration)

Renal impairment prolongs half-life for renally eliminated drugs but may not proportionally extend duration of action 3, 5:

• Metoprolol half-life is unchanged in renal failure since it's hepatically metabolized 5
• Drugs like dabigatran require dose adjustment and extended discontinuation (3-5 days) before surgery in renal impairment 3

Hepatic impairment significantly extends half-life for hepatically metabolized drugs 7, 5:

• Fluoxetine half-life increases to mean 7.6 days in cirrhotic patients (vs 2-3 days normally), with norfluoxetine at 12 days (vs 7-9 days) 7
• Metoprolol half-life can extend up to 7.2 hours depending on severity of hepatic impairment 5

Age-related changes alter half-life in pediatric and geriatric populations 8, 3:

• Neonates have markedly prolonged half-lives for many medications (e.g., phenobarbital 45-500 hours vs 37-73 hours in children) 8
• Geriatric patients may show slightly higher metoprolol concentrations due to decreased metabolism, though this is rarely clinically significant 5

Common Pitfalls

Assuming half-life predicts duration of action is the most frequent error 2:

• A drug with a 3-hour half-life may have effects lasting 12 hours if receptor binding is prolonged
• Conversely, a drug with a 24-hour half-life may lose efficacy after 8 hours if the concentration-response relationship requires high levels 2

Ignoring active metabolites leads to underestimating true duration 1, 2:

• Fluoxetine's active metabolite norfluoxetine has an even longer half-life than the parent drug 7
• The combined effect of parent drug plus metabolite determines actual clinical duration 1

Using terminal half-life to predict accumulation can be misleading 10:

• The "operational multiple dosing half-life" may be significantly shorter than terminal half-life 10
• Accumulation at steady state is often overpredicted when using terminal half-life alone 10