Therapeutic index Type 2 conjugation 0 and 1 order Kinetic
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1. Therapeutic Index (TI)
Definition
The therapeutic index is a relative measure of the safety of a drug. It is defined as the ratio of the median toxic dose (TD50) to the median effective dose (ED50):
TI = TD50 / ED50
- TD50 - dose at which 50% of a population experiences a specific toxic effect
- ED50 - dose at which 50% of a population experiences the desired therapeutic effect
(Schwartz's Principles of Surgery, 11th Ed.; Kaplan & Sadock's Synopsis of Psychiatry)
An equivalent expression using plasma concentrations (Lippincott Pharmacology):
TI = TC50 / EC50 (concentration causing adverse effects in 50% / concentration causing therapeutic effects in 50%)
Interpretation
| TI Value | Meaning | Clinical Implication |
|---|---|---|
| High TI | Wide margin between therapeutic and toxic doses | Safer; wide dosing flexibility |
| Low / Narrow TI | Small margin between therapeutic and toxic doses | Dangerous; requires close monitoring |
Examples:
- Wide TI: Haloperidol, penicillin - wide range of dosing is safe
- Narrow TI: Lithium, warfarin, digoxin, phenytoin - serum level monitoring is mandatory
- Bupropion has a narrow TI with high morbidity/mortality after overdose (Tintinalli's Emergency Medicine)
Key Concept: Therapeutic Window
A therapeutic window exists between the ED50 and TD50. A drug dose must stay within this window to be both effective and non-toxic. (Goodman & Gilman's, 14th Ed.)
2. Type 2 (Phase II) Conjugation Reactions
What Is Phase II Metabolism?
Phase II reactions are biosynthetic (conjugation) reactions that attach an endogenous polar molecule to a drug or its Phase I metabolite, making it more hydrophilic for excretion. These reactions generally inactivate the drug and facilitate elimination. (Goodman & Gilman's; Harper's Biochemistry, 32nd Ed.)
Key Features
- Catalytic rates are significantly faster than Phase I (CYP) reactions
- If a drug undergoes Phase I then Phase II, the rate-limiting step is usually Phase I
- The products are more polar - excreted in urine or bile
Types of Phase II Conjugation
| Reaction | Enzyme | Co-factor/Donor | Example |
|---|---|---|---|
| Glucuronidation | UDP-glucuronosyltransferases (UGTs) | UDP-glucuronic acid (UDP-GA) | Morphine → morphine-3/6-glucuronide; bilirubin; SN-38 (irinotecan metabolite) |
| Sulfation | Sulfotransferases (SULTs) | PAPS (active sulfate, 3'-phosphoadenosine-5'-phosphosulfate) | Acetaminophen sulfate; EtS (ethyl sulfate) |
| Glutathione conjugation | Glutathione S-transferases (GSTs) | Glutathione (GSH) | Electrophilic/toxic intermediates - key detox pathway |
| Acetylation | N-acetyltransferases (NATs) | Acetyl-CoA | Isoniazid, hydralazine, sulfonamides |
| Methylation | Methyltransferases | SAM (S-adenosyl methionine) | Catecholamines, histamine |
| Amino acid conjugation | Various | Glycine, glutamine, taurine | Bile acids, salicylate |
(Harper's Illustrated Biochemistry, 32nd Ed.; Goodman & Gilman's; Costanzo Physiology)
Glucuronidation - Most Important Phase II Reaction
- Carried out by UGTs in the ER of liver and GI tract
- Substrates include drugs, hormones (estrogens, glucocorticoids, thyroxine), bile acids, bilirubin
- Glucuronides can be: (a) excreted in urine via circulation, or (b) excreted in bile via hepatocytes → undergo enterohepatic recirculation when gut bacteria's β-glucuronidase cleave them back
- Per tissue weight, small intestine has higher UGT concentration than liver - important for oral bioavailability prediction
Clinical Notes
- Acetaminophen is metabolized by both glucuronidation and sulfation; gut microbiome can deconjugate the glucuronide metabolite, allowing reabsorption
- Phase II products are typically pharmacologically inactive (but morphine-6-glucuronide is an active exception)
- Bilirubin conjugation defects → hyperbilirubinemia (e.g., Crigler-Najjar Type 1 = severe UGT1A1 deficiency; Type 2 = partial deficiency; Gilbert's syndrome)
3. Zero-Order vs. First-Order Kinetics
First-Order Kinetics
Rate of elimination is proportional to drug concentration.
dA(t)/dt = -k₁ · A(t)
- k₁ = first-order rate constant; units = 1/time (e.g., min⁻¹)
- The fraction of drug eliminated per unit time is constant
- Drug amount declines exponentially over time: A(t) = A₀ · e^(-kt)
- Plasma concentration: C(t) = C₀ · e^(-kt)
- Half-life (t½) is constant - does not depend on the dose or concentration
- Linear pharmacokinetics: steady-state plasma level is directly proportional to dose
(Miller's Anesthesia, 10th Ed.; Goodman & Gilman's)
This is the kinetics of MOST drugs at therapeutic concentrations.
Zero-Order Kinetics
Drug is eliminated at a CONSTANT rate, regardless of plasma concentration (saturation kinetics).
dA(t)/dt = -k₀
- k₀ = zero-order rate constant; units = mass/time (e.g., mg/min)
- Occurs when drug-metabolizing enzymes are saturated
- Half-life is NOT constant - increases as dose increases
- Non-linear pharmacokinetics: small dose increases → disproportionately large rise in plasma concentration (and toxicity risk)
(Miller's Anesthesia; Goodman & Gilman's; Tietz Laboratory Medicine, 7th Ed.)
Comparison Table
| Feature | First-Order | Zero-Order |
|---|---|---|
| Elimination rate | Proportional to concentration | Constant (fixed amount/time) |
| Rate constant units | 1/time (e.g., min⁻¹) | mass/time (e.g., mg/min) |
| Half-life | Constant | Increases with dose |
| Plasma level vs dose | Linear / proportional | Non-linear / disproportionate |
| Graph of concentration | Exponential decay | Linear decline |
| Log[concentration] vs time | Straight line | Curved |
| Metabolic enzymes | Not saturated | Saturated |
| Common? | Most drugs | Few drugs; or toxic concentrations |
Classic Zero-Order Drug Examples
- Ethanol - zero-order at all ordinary concentrations (metabolic capacity saturated)
- Phenytoin - zero-order at therapeutic concentrations; shifts from first-order at low levels
- Salicylate (aspirin) - first-order at therapeutic doses; switches to zero-order when levels exceed 30 mg/dL (Rosen's Emergency Medicine)
- Any drug at toxic overdose concentrations can exhibit zero-order kinetics as enzymes become saturated
Transition Between Orders
At sub-therapeutic concentrations → first-order. As dose increases and enzymes saturate → shifts to zero-order. This has major clinical significance for phenytoin: a small dose increment can cause toxicity because elimination can no longer keep pace. (Katzung Basic & Clinical Pharmacology, 16th Ed.)
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics (14th Ed.) | Lippincott Illustrated Reviews: Pharmacology | Miller's Anesthesia (10th Ed.) | Kaplan & Sadock's Synopsis of Psychiatry | Schwartz's Principles of Surgery (11th Ed.) | Harper's Illustrated Biochemistry (32nd Ed.) | Tietz Textbook of Laboratory Medicine (7th Ed.) | Katzung Basic & Clinical Pharmacology (16th Ed.) | Costanzo Physiology (7th Ed.)
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