Integrated Scientific and

Clinical Pharmacology

From Enzyme Kinetics to

Drug Receptor Interactions
The Biochemical Bases of Pharmacodynamic Parameters
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Objective:
 To understand how Drug (Ligand)-Receptor interactions
in pharmacodynamics (PD) are analogous to the Enzyme-
Substrate reactions (enzyme kinetics models) of
biochemistry
 To demonstrate how Enzyme- Substrate interactions and
Drug-Receptor interactions follow the same biochemical
kinetic principles and have analogous parameters
 To understand the relationship between Ligand-receptor
binding curves Graded dose-response curves
Companion string:
MedPharm Guidebook, Pgs. 17-22
2
 Michaelis-Menten kinetics
[S] = concentration of substrate; V = velocity
 Km is inversely related to affinity
of enzyme for its substrate
 Vmax is directly proportional to enzyme
concentration
 Most enzymatic reactions follow a
Graph demonstrates the Michaelis-Menten
hyperbolic curve (i.e., Michaelis-Menten kinetics model for relationship between an
kinetics) enzyme and a substrate: one of the parameters
 however, enzymatic reactions that exhibit a studies in pharmacokinetics, where the
sigmoid curve usually indicate cooperative substrate is a pharmaceutical drug
kinetics (i.e., hemoglobin)
Km is the M-M constant
Vmax is the maximum volorsity of the reaction

3
 Michaelis-Menten kinetics (2)
 As larger amounts of substrate
are added to a reaction, the
available enzyme binding sites
become filled to the limit of
Vmax
 Beyond this limit the enzyme is From Enzyme kinetics Notes
saturated with substrate and
the reaction rate ceases to
increase
 Saturation curve for an enzyme
rxn showing relation between
substrate concentration and
reaction rate 4
Lineweaver-Burk plot
(the inverse of M-M plots)
 y-intercept , Vmax

 The further to the right the x-intercept (i.e.,

closer to zero), the greater the Km and the
lower the affinity
Expressed mathematically: (only for sake of
completeness)
The y-axis is 1 / Vmax and the x-axis is 1 / [S].
The slope is Km / Vmax.

1 / Vo = (Km / Vmax) • (1 / S) + (1 / Vmax

5
 Enzyme inhibition (1)
 Reversible competitive inhibitors cross
each other competitively, whereas
noncompetitive inhibitors do not

REMEMBER
 increase y-intercept means decrease Vmax

 The further to the right the x-intercept (i.e., closer to

zero), the greater the Km and the lower the affinity

6
Enzyme inhibition(2) Table
Competitive Competitive Noncompetitive
inhibitors, inhibitors, inhibitors
reversible irreversible

Resemble substrate Yes Yes No

Bind active site Yes Yes No
Effect on Vmax Unchanged
Effect on Km Unchanged Unchanged
Overcome by [S] Yes No No
Pharmacodynamics potency efficacy Efficacy

7
 Pharmacology Terminology
 Most drugs evoke effects by interacting with receptors
 Affinity
 Efficacy [pharmacologic] or
 (synonym) Intrinsic activity [molecular]
 Agonists
 Mimic physiologic activation
 Have both high affinity and efficacy
 Antagonists
 Block actions of neurotransmitters or agonists
 Have high affinity, but no efficacy
 Often used as pharmacologic reversal agents 8
What are the differences between competitive
and noncompetitive inhibitors? (1)
 Competitive inhibitors (antagonist) bind to same active site of an
enzyme (receptor) as substrate (ligand/drug) of interest
 In competitive inhibition (antagonism) , the enzyme (receptor) is
bound to either substrate (drug/agonist) or inhibitor (antagonist)
at any given point
 This is because inhibitor (antagonist) closely resembles
substrate
 Competitive inhibition (antagonist) can be overcome by
overwhelming the system with increasing concentrations of
substrate (agonist) , which compete with inhibitor (antagonist) for
active site of catalytic enzyme (receptor)
9
What are the differences between competitive and
noncompetitive inhibitors? (2)
On the other hand,
 Noncompetitive inhibitors (antagonist) bind to alternate sites of
enzyme (receptor) other than the active binding site
 Do not resemble substrate (ligand/drug)
 binding of noncompetitive inhibitor to enzyme (receptor) of interest
distorts enzyme (receptor) such that it can no longer bind to substrate
(ligand/drug)
 Noncompetitive inhibition (antagonism) is often irreversible and
cannot be overcome by saturating system with increasing
concentrations of substrate (ligand/drug)

10
 Receptor binding:
Agonist with Competitive antagonist
Effect
 Shifts curve right ( potency), no
change in efficacy
 Can be overcome by the
concentration of agonist substrate
Example
Diazepam (agonist) + flumazenil
(competitive antagonist) on GABA
receptor

11
 Receptor binding:
Agonist with Non-Competitive antagonist
Effect
 Shifts curve down (efficacy)
 Cannot be overcome by agonist substrate
concentration
Example
 Norepinephrine (agonist) +
Phenoxybenzamine (noncompetitive
antagonist) on α-receptors

12
 Receptor binding:
Agonist with Partial Agonist (alone)
Effect
• Acts at same site as full agonist, but
with lower maximal effect ( efficacy)
• Potency is an independent variable
Example
• Morphine (full agonist) vs.
buprenorphine (partial agonist) at
opioid μ-receptors

13
Efficacy vs. potency
Efficacy RELATIVE EFFICACY

 Maximal effect a drug can produce

 Represented by the y-value (Vmax)
 y-value = Vmax = efficacy
 Unrelated to potency (i.e., efficacious
drugs can have high or low potency)
 Partial agonists have less efficacy than
full agonists

14
 Efficacy vs. potency (2)
Potency RELATIVE POTENCY

 Amount of drug needed for a given

effect
 potency (EC50) = drug needed
 Represented by the x-value (EC50)
 Left-shifting = EC50 = potency
 Unrelated to efficacy (i.e., potent
drugs can have high or low efficacy)

15
Ligand-receptor binding curves

A. Linear B. Semilogarithmic

A. Linear graphs of drug-receptor binding for two drugs with different values of Kd.
B. Semilogarithmic graphs of the same drug-receptor binding. Kd = equilibrium dissociation constant for a
given drug-receptor interaction. A lower Kd indicates a tighter drug-receptor interaction (higher affinity). Drug
A, which has the lower Kd, will bind a higher proportion of total receptors than Drug B at any given drug
concentration. Notice that Kd corresponds to the ligand concentration [L] at which 50% of receptors are bound
(occupied) by ligand. [L] is concentration of free (unbound) ligand (drug), [LR] is concentration of ligand-
receptor complexes, and [Ro] is total concentration of occupied and unoccupied receptors. Thus, [LR] /[R0] is
the fractional occupancy of receptors, or fraction of total receptors that are occupied (bound) by ligand.
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy
16
Cairo CW, Simon JB, Golan DE. (Eds.); LLW 2012, Pgs. 17-27
Graded dose-response curves

A. Linear B. Semilogarithmic

Graded dose-response curves demonstrate effect of a drug as a function of its concentration.

A. Linear graphs of graded dose-response curves for two drugs.
B. Semilogarithmic graphs of same dose-response curves. Note close resemblance to Ligand-receptor binding
curves: fraction of occupied receptors [LR]/[R0] has been replaced by fractional effect E/Emax, where E is a
quantifiable response to a drug . EC50 is potency of t drug, or concentration at which the drug elicits 50% of
its maximal effect. In the figure, Drug A is more potent than Drug B because it elicits a half-maximal effect at
a lower concentration than Drug B. Drugs A and B exhibit the same efficacy Note that potency and efficacy
are not intrinsically related-a drug can be extremely potent but have little efficacy, and vice versa.
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy
Cairo CW, Simon JB, Golan DE. (Eds.); LLW 2012, Pgs. 17-27
Therapeutic index (TI)
Measurement of drug safety
TD50 (median toxic dose)
TI = ED50 (median effective dose)

Therapeutic window is
measure of clinical drug
effectiveness for a patient
 Therapeutic Index = TD50 / ED50
 Safer drugs have higher TI values
 Drugs with lower TI values include digoxin, lithium, theophylline, and
warfarin
 LD50 (lethal median dose) often replaces TD50 in animal studies 18
19
Further study:
 eNotes: GP- General Principles of Drug Action

 Drug-Receptor Interactions, Morris ZS, Golan DE and (or)

 Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and

Concentration-Response Relationships

 Enzyme kinetics Notes

 MedPharm Wiki| PK and PD, Pgs. 73-88

 Pharmacology Course Website

20