Pharmacokinetics: Excretion & Drug Elimination

Page 15 - Excretion

Key Principle

• Drugs excreted are ionised / water soluble / polar forms.

Major Organs of Excretion

• Kidneys - most common (m/c) organ for excretion
• Liver - m/c organ for metabolism (not excretion)
• Minor routes: saliva, sweat

Renal Excretion - Two Mechanisms

Key insight: Tubular secretion is the dominant route (80%) and can handle even protein-bound drug.

• Filtration depends on GFR → gives a constant rate of excretion

Rate of Drug Elimination (RDE)

• Amount of drug eliminated per hour from the body

• Plasma concentration = concentration of drug in each ml of plasma (mg/ml)
• Clearance = volume of plasma cleared of drug per hour (ml/hr)

Page 16 - Drug Dosing & Half-Life

Drug Dosing Types

• Infusion rate = Plasma concentration × Clearance
• Plasma conc rises until infusion rate = rate of elimination → Steady State
• 4-5 half-lives (T½) required to reach steady state
• Steady state depends on Volume of Distribution (Vd)

1. Phase I (Rising): Absorption > Excretion
2. Phase II (Plateau): Infusion rate = Rate of elimination → Steady state
3. Phase III (Declining): Excretion > Absorption

• Dose given periodically to maintain steady-state plasma concentration
• Depends on Clearance

• f = Bioavailability (f = 1 for IV routes)

Half-Life (T½)

• Time taken for plasma drug concentration to decrease by 50%

• T½ ∝ Vd / Cl
• Elimination constant (K_el) = Cl / Vd

Page 17 - Kinetics of Drug Elimination

Zero-Order vs. First-Order Kinetics

High-Yield Memory Points

1. Kidneys = excretion; Liver = metabolism (a common exam trap)
2. Tubular secretion (80%) > filtration (20%) - and secretion can handle protein-bound drug
3. Phenytoin is the classic exam drug for zero-order (also theophylline, warfarin) - saturation causes disproportionate toxicity
4. 4-5 half-lives to reach steady state - applies to both accumulation and elimination
5. Loading dose depends on Vd; Maintenance dose depends on Clearance
6. T½ = 0.693 × Vd / Cl - must memorize this formula

Page 15 - Pharmacokinetics: Excretion

What is Excretion?

• Non-polar drugs are lipid-soluble → they get reabsorbed from the kidney tubule → NOT easily excreted → that's why the liver first converts them into polar metabolites before the kidney can eliminate them.
• Polar/ionised drugs → cannot cross lipid membranes → stay in tubular fluid → get excreted in urine.

Major Organs of Excretion

Exam trap: Kidneys = excretion. Liver = metabolism. These are often swapped in MCQs.

How the Kidney Excretes Drugs - Two Mechanisms

1. Glomerular Filtration (20% contribution)

• Blood enters the glomerulus under pressure → small molecules are pushed through the filtration membrane into the Bowman's capsule.
• Only free (unbound) drug is filtered - because protein-bound drug is too large to pass through.
• Why? The glomerular basement membrane carries a negative charge → it repels negatively charged plasma proteins → protein-bound drug (negative charge) is blocked.
• Filtration depends entirely on GFR (Glomerular Filtration Rate) → if GFR is constant, excretion by filtration is constant.
• Contributes only 20% of total renal drug excretion.

2. Active Tubular Secretion (80% contribution)

• In the proximal tubule, carrier proteins (transporters) actively pump drugs from the blood into the tubular lumen.
• This is an active, energy-dependent process - uses ATP.
• Both free AND protein-bound drug can be secreted - the transporters "pull" drug off the plasma proteins and secrete it.
• This is why tubular secretion dominates - it doesn't care whether the drug is bound or free.
• Contributes 80% of total renal drug excretion.
• Two major transporter systems exist: one for organic anions (acidic drugs - e.g., penicillin, furosemide) and one for organic cations (basic drugs - e.g., dopamine, histamine). - Goodman & Gilman's, Renal Excretion section

The Table from Your Notes Explained

Rate of Drug Elimination (RDE)

• Plasma Concentration (PC): How much drug is present in each ml of plasma right now - in mg/ml.
• Clearance (Cl): Volume of plasma that is completely cleared of drug per hour - in ml/hr.

Drug Dosing (intro only on this page)

• a. Continuous IV infusion - drug is given as a continuous drip
• b. Intermittent dosing - drug is given at intervals (e.g., tablets, injections every 8 hours)

Page 16 - Drug Dosing, Steady State & Half-Life

A. Continuous IV Infusion (= Loading Dose concept)

The Three Phases (Concentration-Time Curve)

• Infusion is pumping drug in faster than the body can eliminate it.
• Plasma concentration rises gradually.

• The amount coming in equals the amount going out.
• Plasma concentration plateaus - this is the steady state.
• This is the target in clinical practice - stable, predictable plasma levels.

• Infusion stopped → no more drug coming in → elimination continues → plasma concentration falls.

Key Formulas

How Long to Reach Steady State?

• 4-5 half-lives are required to reach steady-state plasma concentration.
• This is a universal rule regardless of the drug - it comes from the mathematics of exponential decay.
  • After 1 half-life → 50% of steady state
  • After 2 half-lives → 75%
  • After 3 half-lives → 87.5%
  • After 4 half-lives → 93.75%
  • After 5 half-lives → ~97% ≈ steady state
• Steady state depends on Volume of Distribution (Vd) - because Vd determines how the drug distributes throughout the body, affecting how high or low the plasma level is.

B. Intermittent Dosing (= Maintenance Dose)

• Also called maintenance dose because it maintains the plasma concentration within the therapeutic range.
• Depends on Clearance - you need to replace exactly how much the body clears between doses.

• PC = Target plasma concentration you want to maintain
• Cl = Clearance (how fast the body eliminates the drug)
• Time = Dosing interval (e.g., 8 hours)
• f = Bioavailability (what fraction of the oral dose actually reaches systemic circulation; f = 1 for IV)

Half-Life (T½)

Definition

Formula

What Determines T½?

• Large Vd → longer T½: If a drug distributes widely into tissues, less drug stays in plasma at any time → it takes longer to fall by 50% in plasma. (E.g., chloroquine has a huge Vd → T½ of weeks.)
• High Clearance → shorter T½: The faster the body clears drug, the more quickly plasma levels fall.
• Goodman & Gilman's confirms: "T½ changes as a function of both clearance and volume of distribution: t½ = 0.693 × Vss/CL"

Elimination Rate Constant (K_el)

• This is the fraction of drug eliminated per unit time.
• Higher K_el = drug eliminated faster = shorter T½.
• T½ and K_el are inversely related: T½ = 0.693 / K_el.

Page 17 - Kinetics of Drug Elimination: Zero-Order vs. First-Order

The Core Concept

• First-order kinetics - most drugs, most of the time
• Zero-order kinetics - a few drugs with easily saturated elimination systems

First-Order Kinetics (n = 1)

• If you have 100 mg → 50 mg eliminated in hour 1
• If you have 50 mg → 25 mg eliminated in hour 1
• The rate changes with concentration, but the fraction (proportion) stays constant.

• T½ is constant regardless of dose
• Clearance is constant
• If you double the dose → plasma concentration doubles proportionately (linear relationship)
• Safe and predictable - easy to dose

Zero-Order Kinetics (n = 0)

• Elimination system is already saturated - working at maximum capacity.
• It can only eliminate a fixed number of mg per hour, regardless of how much drug is present.
• As dose increases → plasma concentration rises disproportionately → high risk of toxicity.

• T½ increases as dose increases (not constant)
• Clearance decreases as dose increases
• Even a small dose increase can cause a huge spike in plasma concentration → toxicity

• Alcohol: Liver has a limited amount of alcohol dehydrogenase → saturated even at moderate doses → classic zero-order.
• Phenytoin: At therapeutic doses, CYP2C9/2C19 enzymes become saturated → shift from first-order to zero-order. Katzung's confirms: "As the dose increases, there is saturation of metabolism and a shift from first-order to zero-order kinetics in which a constant quantity per unit time is metabolized. A small increase in dose can result in a large increase in concentration."

The "Exception to the Rule" - Pseudozero Order

• Zero-order drugs at LOW doses → enzymes not yet saturated → follow first-order kinetics
  • Called pseudozero order because the drug behaves like first-order but is classified as zero-order
  • E.g., phenytoin at subtherapeutic doses follows first-order; only at therapeutic/high doses does it flip to zero-order
• First-order drugs at HIGH doses → enzymes get saturated → follow zero-order kinetics
  • E.g., gabapentin at very high doses saturates gut absorption transporters → absorption becomes zero-order

Zero-Order Drug Examples (Must Memorise)

Side-by-Side Comparison Table

Putting It All Together - Clinical Example

1. At low doses: first-order kinetics → safe, predictable
2. At therapeutic doses (10-20 mcg/ml): enzymes saturating → shifting to zero-order
3. A doctor increases dose by 10% → plasma level rises by 40-50% instead of 10% → nystagmus, ataxia, confusion (phenytoin toxicity)
4. This is why phenytoin requires therapeutic drug monitoring (TDM) and very careful dose titration