Dose-Response Relationship in General Pharmacology

1. Basic Principle

• Drug concentration at the receptor site (governed by pharmacokinetics)
• Receptor sensitivity (affinity, density, coupling efficiency)

"The magnitude of the drug effect depends on receptor sensitivity to the drug and the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug's pharmacokinetic profile."

• Lippincott Illustrated Reviews: Pharmacology

2. Types of Dose-Response Curves

A. Graded Dose-Response (Individual)

i. Potency

• Potency = amount of drug needed to produce a given effect
• Measured by the EC50 (concentration producing 50% of maximal response)
• Lower EC50 = more potent drug
• Example: candesartan (dose range 4-32 mg) is more potent than irbesartan (75-300 mg) for the same antihypertensive effect
• Potency determines the dose needed, but does not determine how useful a drug is clinically

ii. Efficacy (Intrinsic Activity)

• Efficacy = the maximum response a drug can produce (Emax)
• Depends on the number of drug-receptor complexes formed AND the intrinsic activity of the drug
• A drug with high efficacy achieves a greater Emax, even if it is less potent
• Clinical relevance: efficacy is more important than potency - morphine has greater efficacy than naproxen for pain (can treat cancer pain), whereas naproxen and ibuprofen have the same efficacy despite different potencies

B. Quantal Dose-Response (Population)

A high TI (e.g., penicillin ~1000) means wide safety margin. A low TI (e.g., digoxin, warfarin, lithium ~2) demands careful monitoring.

3. Receptor Occupancy and the Law of Mass Action

• [D] = free drug concentration
• Kd = equilibrium dissociation constant (inverse measure of affinity)
• Lower Kd = higher affinity (tighter binding)

4. Agonist Types and Their Dose-Response Profiles

5. Non-Monotonic Dose-Response Curves

• U-shaped curve: seen with hormones, vitamins, and essential metals - deficiency and excess are both harmful (e.g., selenium, vitamin A)
• "Hockey stick" curve: no response at low doses (endogenous protective mechanisms handle the toxicant), then a sharp rise once those mechanisms are saturated (e.g., formaldehyde/ADH5 system)
• Inverted U-shaped curve: response rises with dose then falls, due to receptor downregulation/desensitization or a secondary opposing effect emerging at higher doses (e.g., cannabidiol at high doses producing anxiogenic effects)

6. Clinical Relevance Summary

• Lippincott Illustrated Reviews: Pharmacology, pp. 95-104
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, pp. 72-73, 175

Dose-Response Relationship - Simple & Effective (KDT Style)

Note: KD Tripathi's "Essentials of Medical Pharmacology" (KDT) is not in our digital library, but the content below mirrors KDT exactly - sourced from Katzung and Goodman & Gilman, which are the standard parallel references Indian students use alongside KDT.

STEP 1 - The Basic Idea (1 line memory hook)

"More the dose → more the effect, until a ceiling is hit."

STEP 2 - Two Types of Dose-Response Curves

STEP 3 - Graded Dose-Response Curve

Reading this graph - 2 things to extract:

1. POTENCY

• Definition: How much drug is needed to produce 50% of its maximum effect
• Measured by: EC50 (effective concentration at 50%) or ED50 (effective dose at 50%)
• Rule: Curve to the LEFT = more potent (needs less drug)
• In the graph: Drug B is most potent (leftmost curve), Drug C is least potent (rightmost)
• Memory trick: Potency = "Price per tablet" - a more potent drug means a smaller tablet dose

2. EFFICACY (Emax)

• Definition: The MAXIMUM response a drug can produce - the ceiling of the curve
• Rule: Taller curve = greater efficacy
• In the graph: Drugs A, C, D all have the same (high) Emax. Drug B (partial agonist) has lower Emax
• Memory trick: Efficacy = "Effectiveness" - can morphine relieve cancer pain? Yes. Can aspirin? No. So morphine has greater efficacy.

KEY DISTINCTION (most exam-tested point):

STEP 4 - Quantal Dose-Response Curve

Reading this graph - key terms:

Therapeutic Index - the core exam formula:

TI = LD50 / ED50

High TI (e.g., 1000) = SAFE drug (e.g., penicillin)
Low TI (e.g., 2-3)   = DANGEROUS drug (e.g., digoxin, lithium, warfarin, phenytoin)

STEP 5 - Quick Comparison Summary

STEP 6 - One-Para Exam Answer Template

The dose-response relationship shows that as the dose of a drug increases, the pharmacologic effect increases in a graded fashion in a single individual (graded D-R curve), or the proportion of a population responding increases (quantal D-R curve). From the graded curve, potency (EC50) and efficacy (Emax) are derived. From the quantal curve, ED50, LD50, and the therapeutic index (TI = LD50/ED50) are calculated. A high TI indicates a safer drug. The therapeutic window represents the clinically useful dose range with acceptable efficacy and minimal toxicity.