Pharmacology 3620 Lecture Notes - Lecture 6: Imatinib, Ionic Bonding, Hydrogen Bond
1 May 2018
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Lecture 006: Pharmacodynamics I
Objectives
● Define 4 types of interactions between a drug and its receptor
● Apply the law of mass action as it applies to drug-receptor binding
● Describe and apply Kd as it pertains to drug receptor interactions
● Calculate the fractional occupancy of a receptor when given relevant parameters
● Describe the saturable nature of drug receptor binding with the use of dose response
curves
● Differentiate between graded and quantal responses
● Define potency, efficacy, affinity and intrinsic activity and differentiate these
parameters on a dose-response curve
● Define the concept of spare receptors
● Use quantal dose response information to calculate the therapeutic index
● Differentiate between full and partial agonists
What is Pharmacodynamics?
● The quantitative description of the effect of a drug on the body
○ What the drugs do to the body (rather than the body on the drug)
○ Want the drug to have an effect on the patient
■ How does the drug help the patient?
● Most (but not all) drugs exert their effects by binding to specialized macromolecules
○ Most of drug targets are receptors and enzymes
The Relationship Between PK and PD
● Both pharmacokinetics and
pharmacodynamics are very
important
○ Pharmacokinetics
■ Needs to be
therapeutically useful
and non-toxic
■ Give a dose of the
drug -> get a concentration of drug in the blood
■ Want to know the concentration of the drug at the site of action
■ That has an impact on the effect of the drug
○ Pharmacodynamics
■ Drug not effective at treating disease
■ In pharmacodynamics we are interested in
● What happens at the site of action?
● What are those effects?
The Basics of Drug Receptors
find more resources at oneclass.com
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● Drugs are a “signal” that we send to our body to change a response
○ Disease occurs when a response in the body is abnormal
● Receptors are detectors that receive the signal
○ What drugs that changes something to have a therapeutic effect
● In the simplest schematic, when receptors reside empty, they do not influence
intracellular processes
○ Needs to have a drug binding to a receptor to have an effect
○ Receptor is activated by drug binding and produces a biological response
● Many drugs either:
○ Mimic an endogenous ligand
○ Blocks the endogenous ligand from binding
● Note: Ligand is a molecule that binds to a receptor (a ligand can be a drug OR a
endogenous molecules
Types of Interactions Between Drugs and Receptors
● Need to know how the body works in its normal state to treat the disease
● Since drugs are usually chemicals, they interact with receptor using bonds
○ Van der waals, hydrogen bonding, ionic bonding, covalent bonding
○ Usually a COMBINATIONS of different types of bonds that causes drug-receptor
binding
■ Rare to have only one type of bond
○ Many weak bonds make up a drug-receptor interaction
● Most interactions are a combination of van der waals and hydrogen bonding
○ ionic and covalent bonding are rare
● Number and type of the interaction generate how strong the interaction is
○ Strength: Van der waals < hydrogen < ionic < covalent
Example of a drug-receptor binding
● Imatinib fits into the Bcr-Abl kinase’s binding pocket
○ This means that imatinib has a specific shape
● Blue shaded structure is imatinib
○ The amino acid that makes up the binding pocket determines how well the drug
will bind to its target
○ Lots of hydrogen bonds and van der Waals forces in action
■ Multiple different hydrogen bond/van der waals created by the amino
acids in the binding pocket creates the binding interaction
The Relationship Between Drug Concentration and Receptor Occupancy
● Cells have a finite number of receptors
find more resources at oneclass.com
find more resources at oneclass.com
kON
Drug (D) + Receptor (R) ⇋ Drug-Receptor Complex (DR) -----> biological effect
kOFF
● Most drug binding events obey the Law of Mass Action:
○ Rate of reaction depends on the concentration of the reactants
○ KON: rate of association (# binding events/time unit)
○ KOFF: rate of dissociation (# dissociations events/time unit)
○ Usually drug binding is reversible (equilibrium)
● Drug-receptor complex(DR)
○ Usually the one that promotes the biological action
● Assumptions of this model:
1. Binding is reversible
2. All receptor are equally accessible to drugs
3. Neither drug or receptor is altered by the binding
■ Not true!
■ Usually when the drug binds to the receptor there is a change in the
conformation of the receptor (helps mediate the action of the drug)
● The more drug you have
○ KON >>> KOFF (shifts the equilibrium to the right)
○ Thus the greater the DR, and biological effect
● However, drug metabolism removes the free drug
○ KOFF >>> KON (shifts the equilibrium left)
○ Less DR, less biological effect
The Equilibrium DIssociation Constant (Kd)
● Kd is calculated as KOFF / KON
● Kd is more influenced by its dissociation rate
(KOFF ) rather than its association rate (KON)
● Kd is expressed in units of concentration
(nM/μM)
● Kd: the concentration of the drug when 50%
of the available receptors at equilibrium are
occupied by the drug
○ Calculated experimentally
■ Change the dose of the drug (x-axis) and measure the amount of drug
molecules are bound (y-axis)
■ Plot this
● THE SMALLER THE Kd THE HIGHER THE AFFINITY THE DRUG HAS FOR THE
RECEPTOR
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Define 4 types of interactions between a drug and its receptor. Apply the law of mass action as it applies to drug-receptor binding. Describe and apply kd as it pertains to drug receptor interactions. Calculate the fractional occupancy of a receptor when given relevant parameters. Describe the saturable nature of drug receptor binding with the use of dose response curves. Define potency, efficacy, affinity and intrinsic activity and differentiate these parameters on a dose-response curve. Use quantal dose response information to calculate the therapeutic index. The quantitative description of the effect of a drug on the body. What the drugs do to the body (rather than the body on the drug) Want the drug to have an effect on the patient. Most (but not all) drugs exert their effects by binding to specialized macromolecules. Most of drug targets are receptors and enzymes. Both pharmacokinetics and pharmacodynamics are very important. Needs to be therapeutically useful and non-toxic.
