Pharmacokinetics & Enzyme Kinetics

Understanding drug movement, metabolism, and enzyme behavior

Key Definitions: What's What?

Pharmacodynamics

What a drug DOES at its target site

Concentration at site of action + Pharmacologic effect
Think: the drug hits the receptor, what happens?

Pharmacokinetics

How the body MOVES the drug around

Drug movement IN, AROUND, and OUT of the body
Think: absorption → distribution → metabolism → elimination

The Big Rule: Rate-Limiting Enzymes

Every rate-limiting enzyme produces a sigmoidal (S-shaped) kinetic curve because of:

COOPERATIVITY
One substrate binding makes the next substrate bind easier (like hemoglobin)

First-Order vs Zero-Order Elimination

FIRST-ORDER Kinetics (The Default)

Enzyme active sites are NOT saturated → there's room for more substrate

  • As [substrate] increases → Vmax increases (linear relationship)
  • Body metabolizes a constant FRACTION/PROPORTION (20%, 30%, etc.)
  • Test clue: they say "proportion" or "percent eliminated per hour"
  • Example: Kidney GFR is ALWAYS first-order (passive filtration, can't saturate)

ZERO-ORDER Kinetics (The Dangerous One)

Enzyme active sites are ALL SATURATED → no room for more

  • [Substrate] no longer affects Vmax (flat line at top)
  • Body metabolizes a constant NUMBER/AMOUNT (mg/mL per hour)
  • Test clue: they give an AMOUNT, not a percentage
  • Important: Transport proteins in kidney are saturable → zero-order
Zero-Order Transport Max in Kidney:
Glucose transport max = 126 mg/dL
Above this = glucose in urine (prediabetes: 100–126)

Zero-Order Drugs (MEMORIZE THESE)

Alcohol, Aspirin, Phenytoin
Dangerous! Easy to overdose. Even MORE dangerous in liver/kidney disease.

Loading dose trick: Bypasses first-order kinetics → gets drug to steady state (zero-order) faster

Km and Vmax: The Core Metrics

Km = Affinity = Potency

Km is the concentration at ½ Vmax
Km = 1/affinity = 1/potency
  • High Km → Low affinity, Low potency (enzyme doesn't "like" the substrate)
  • Low Km → High affinity, High potency (enzyme "loves" the substrate)
  • Fun fact: Brain has the lowest Km for any substrate (highly selective)

Vmax = Speed = Efficacy

Vmax is how FAST the reaction goes when the enzyme is saturated
Think: the speed limit when you've got a full team working
  • Vmax reflects the amount of enzyme present
  • More enzyme = higher Vmax

[S] = Substrate Concentration

How much "fuel" you're feeding to the enzyme

Quick Check
If an enzyme has a Km of 2 mM, what does this tell you?
A) The enzyme has high affinity for its substrate
B) The enzyme has low affinity for its substrate
C) The enzyme cannot bind substrate

Michaelis-Menten & Lineweaver-Burk Graphs

Michaelis-Menten Curve (The Curved One)

Michaelis-Menten: Reaction Rate vs Substrate Concentration
[Substrate] V Vmax Km ½V

Key: Hyperbolic (curved) shape. Km point shows ½ Vmax. Reaction rate approaches Vmax asymptotically.

Lineweaver-Burk Plot (The Straight One)

Lineweaver-Burk: Double Reciprocal (1/V vs 1/[S])
1/[S] 1/V 1/Vmax -1/Km

Key: Straight line. Y-intercept = 1/Vmax, X-intercept = -1/Km, Slope = Km/Vmax

Why Lineweaver-Burk?
Makes enzyme inhibition patterns OBVIOUS (different line slopes = different inhibition types)

Competitive vs Non-Competitive Inhibition

Interactive Graph: Toggle Inhibition Type

Michaelis-Menten: No Inhibition vs Inhibition
[S] V Vmax Normal

Comparison Table

Property Competitive Non-Competitive
Binding Site SAME active site as substrate DIFFERENT allosteric site
Similarity Similar properties to substrate Different properties
Effect on Km ↑Km (decreased affinity) Km stays the same
Effect on Vmax Vmax stays the same ↓Vmax (decreased efficacy)
Can Add Substrate to Overcome? YES (↑Km but can add more) NO (can't overcome it)
Real-World Use 90% of drugs are competitive Deadly diseases (worse prognosis than side effects)
Overdose REVERSIBLE IRREVERSIBLE
Challenge Question
A drug inhibits an enzyme by binding to an allosteric site, causing Vmax to decrease but Km to stay the same. What type of inhibition is this?
A) Competitive inhibition
B) Non-competitive inhibition
C) Irreversible inhibition

Drug Levels: Peak and Trough

Peak Level

Highest drug concentration in blood
Measured: 4 hours post-dose
Corresponds to: The DOSE (how much you give)
  • Peak is too high? → Lower the dose
  • Peak is too low? → Increase the dose

Trough Level

Lowest drug concentration in blood
Measured: 1–2 hours before next dose
Corresponds to: The FREQUENCY (how often you give it)
  • Trough is too high? → Give drug less often (increase interval)
  • Trough is too low? → Drug is washing out too fast (something's wrong)

Kidney Evaluation

Best metric: Creatinine Clearance (CrCl)
But it's impractical (requires 24-hour urine collection)
  • Use for: Water-soluble or charged drugs (pass through kidneys)
  • Don't use: Fat-soluble drugs (go to liver instead)

Liver Metabolism & Drug Clearance

Drug Type → Route of Metabolism

  • Fat-soluble drugs: Go to liver (large molecules, harder to eliminate)
  • Water-soluble drugs: Go to kidney (easy to filter out)

Phase I: Mixed Function Oxidases

Use O₂ to add Sulfur, Nitrogen, or Oxygen atoms
Goal: Make fat-soluble drug more water-soluble
  • P450 system: Most important enzyme system for drug metabolism
  • Critical detail: P450 decreases with age → elderly struggle with fat-soluble drugs

Phase II: Conjugation

Add a large water-soluble molecule to fat-soluble drug
Definition: "Conjugate" = adding large molecule (like glucose to bilirubin)

Conjugation Methods (in order of frequency):

Method Frequency Why?
Acetylation ~90% of the time Body has lots of acetyl-CoA from Krebs cycle
Adenylation Also available Using adenosine derivatives
Sulfate Also available Sulfate groups readily available
Phosphorylation Also available Phosphate groups readily available
Challenge Question
An elderly patient taking a fat-soluble drug shows signs of toxicity at normal doses. Why might this occur?
A) P450 enzyme activity decreases with age, reducing drug clearance
B) Elderly patients absorb more drugs from the GI tract
C) Water-soluble drugs accumulate in elderly patients

Alcohol Clearance & Tolerance

Alcohol is Zero-Order

Alcohol clearance = 100 mg/dL per hour
This is FIXED. Nothing speeds it up.
  • BAL 100 → takes 1 hour to clear
  • BAL 200 → takes 2 hours to clear
  • BAL 250 → takes 2.5 hours to clear
  • Clinical reality: ER lets alcoholics sleep it off, then they sign out AMA

Tolerance = Enzyme Induction

Chronic alcohol use induces more enzymes
More enzymes = more first-order capacity = can drink 3x more

Cross-Tolerance: The Danger

Similar chemicals use the SAME enzymes
Example: Alcohol → GABA drugs → Benzodiazepines
  • Result: Alcoholics need HIGHER benzodiazepine doses to feel sedated
  • Danger: If they go through withdrawal, their elevated enzyme capacity suddenly becomes dangerous (drugs clear too fast)

Effects of Alcohol Acidosis (Memorize These 4)

↑GABA effect — More sedation
Denatures proteins — Tissue damage
Hyperkalemia → Arrhythmias — Cardiac risk
Kussmaul breathing — Metabolic acidosis compensation

Key Definitions

  • Drug abuse: Use causes social impairment (but not physical dependence)
  • Drug addiction: Withdrawal symptoms occur when you stop
  • Chemical dependence: Needs drug to feel normal (not necessarily addiction)

Hemoglobin: Quaternary Structure Intro

Fun Fact: First Quaternary Protein

Hemoglobin was the FIRST quaternary protein discovered
(NOT an enzyme — just a carrier protein)

Structure: 4 Subunits

Each subunit contains:
  • Heme molecule: Iron (Fe) inside a porphyrin ring
  • Globin chain: Protein surrounding the heme

Hemoglobin Types (Memorize These)

Type Chains Frequency in Adults
Hb A (Adult) 2α + 2β ~98%
Hb A2 2α + 2δ ~2%
Hb F (Fetal) 2α + 2γ Fetal only (but persists in some adults)
Why This Matters:
Different hemoglobin types have different oxygen affinities. Fetal Hb (Hb F) has higher affinity, allowing oxygen transfer from mother to fetus across the placenta.

Knowledge Check: Randomized Quiz

Question 1 / 10 Score: 0/10