PharmacologyTier 1Medical Sciences concept

Determinants of steady-state drug concentration (clearance vs half-life vs Vd)

Core concept

```

Css = (F x Dose) / (CL x tau)

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Clearance is the sole determinant of the steady-state concentration for a given dosing rate
- Halve clearance -> double Css
- Change the dose or interval -> Css changes proportionally
Half-life determines the TIME to steady state, not the level
- t-half = 0.693 x Vd / CL - a derived parameter, not an independent one
- ~4-5 half-lives to reach 94-97% of steady state, and the same to wash out
Vd determines the loading dose, and nothing about Css

```

Loading dose = (Vd x target Cp) / F

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Want to change	Change
Steady-state level	Dose or interval (or clearance changes)
Time to reach it	Give a loading dose - the only way
Peak-trough swing	Interval, not total dose

Fractions of steady state: 1 t-half = 50%, 2 = 75%, 3 = 87.5%, 4 = 94%, 5 = 97%
Vd is apparent, not anatomical - the volume required to contain the dose at the measured plasma concentration
- Low Vd (<0.2 L/kg) - plasma-confined, highly protein-bound (warfarin, aspirin, gentamicin ~0.3)
- High Vd (>10 L/kg) - tissue-sequestered (digoxin ~7, amiodarone ~60, TCAs ~20, chloroquine ~200)
- High Vd -> not removable by dialysis
Constant dosing rate -> first-order kinetics -> proportional change
- Exception: zero-order (saturable) kinetics - phenytoin, ethanol, high-dose salicylate, theophylline
- Phenytoin: a small dose increase near saturation causes a disproportionate level rise; increment by 25-50 mg, not 100 mg
Continuous infusion: loading dose sets the starting level, infusion rate sets the plateau
Amiodarone - t-half ~50 days -> months to steady state without loading, months to wash out after stopping
Renal impairment reduces CL of renally cleared drugs -> inc Css and inc t-half, so both level and time-to-plateau rise

A trough level taken before steady state is uninterpretable - wait 4-5 half-lives, or interpret with that caveat
- Digoxin (t-half ~36 h) -> steady state at ~7 days; sample at least 6 h post dose
Load when the therapeutic effect cannot wait - amiodarone, digoxin, phenytoin, vancomycin, gentamicin in sepsis
- Loading dose depends on Vd only, so it is unchanged in renal failure; the maintenance dose is what falls
Falling GFR raises the level of a renally cleared drug even with an unchanged dose - the mechanism of digoxin, gabapentin, metformin and DOAC accumulation in AKI
Adding a CYP inhibitor lowers clearance -> Css rises to a new plateau over 4-5 half-lives - toxicity appears days after the interacting drug is started

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