NUR 2234: Advanced Pharmacology
Module 1


Learning Objectives

  1. Distinguish between pharmacodynamics and pharmacokinetics
  2. Describe drug movement throughout the body
  3. Identify barriers and obstacles for drugs in the body
  4. Explain concepts of kinetics and their clinical importance
  5. Identify variables affecting kinetics and their relation to drug dosing
  6. Explain toxicities and their relation to on-target or off-target responses

Table of Contents


Drug-Receptor Model

Protein Structure

Theoretically drugs can bind to almost any 3-D target. Desired effects (as well as adverse effects) occur when drugs bind to selected target molecules or receptors. This binding causes biochemical or physiological changes within the body. Receptors are macromolecules that mediate the biochemical or physiological changes that occur when the drug binds.

Receptors are generally proteins. Proteins have 4 major levels of structure:

Different parts of the protein have different affinities for water:

Let's take a look at how protein structure develops:

Mod1_Slide04 image.jpg

Drug Binding

The binding site on a receptor is where the drug actually binds. Binding is affected by many different types of interactions:

Now let's view an animation on drug receptor binding:

The animation above shows how drugs bind to cells.

The combination of all the interactions are what gives the drug its specificity. The favorability of the drug-receptor interaction is the affinity of the drug for the receptor (more later). Binding is rarely caused by one interaction. Stable Drug-receptor complexes usually have multiple interactions.

The molecular structure of a drug is what gives the drug its physical and chemical properties that determine how it will bind to the receptor. Important factors are:

Warfarin-S enantiomer 4x more potent vs. R enantiomer due to it's ability to bind to the receptor.

Let's take a look at a drug molecule as it binds to its receptor in a protein. In this case it inhibits the enzymes action, but drugs can also stimulate action.


Active Site

In some cases drugs bind to sites that have enzymatic activity. This active site is where enzymatic transformation is catalyzed. If the drug inhibits binding of the normal substrate is inhibits the enzymes action. In other cases the drug may not bind to the active site.

In these cases the drug may change the shape of the receptor to increase or decrease substrate binding. Drugs can also bind and change the conformation of the receptor referred to as induced fit:

The structure of a drug can affect its ability to get to the receptor because of the plasma membrane. Highly water-soluble drugs are generally less able to pass through the plasma membrane or they need membrane channels or transporters. Highly lipophilic drugs cross easily and have good access to intracellular targets.

Drug Design

Let's now look at the drug receptor relationship in an equation type relationship:

k1 = association constant (drug on)

k2 = dissociation constant (drug off)

k1 / k2 = AFFINITY


This equation represents a drug binding to a receptor and forming a drug receptor complex. Please note this is not a static process and may or may not elicit a response. We will talk more about this later in pharmacodynamics.

In general, the more restricted the cell-type distribution, the more selective the drug will be, and the more receptor-effector coupling mechanisms differ among the cell types targeted, the more selective the drug will be.

Receptor Types

Now we can take a look at 4 common types of receptors and get a visual idea of the process of drug binding to its receptor:



Let's look at regulation of an ion channel. This is an example of a Ligand-gated.


Now let's look at G-protein coupled receptors and what happens when an agonist binds to the receptor:


Here we'll take a look at how a steroid hormone can diffuse through the cell membrane to act at an intercellular target receptor:


Cellular Regulation

Now let's take a look at how cells can up regulate and down regulate receptors:


Not all drugs interact with receptors. Osmotic diuretics act on ion channels and change osmolarity of nephron directly. Antacids absorb or chemically neutralize acid.

Self Check Questions: Drug-Receptor Model

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Dose Response Relationships

Let's look at what dose-relationship curves look like on a linear and semi-logarithmic scale:


Let's first look at G-graded dose response curves:


Now we'll look at Quantal dose response curves and critical points used in determining dosing and safety:


Let's revisit our drug receptor complex equation and the relationships it represents:

drug + receptor drug-receptor cplx.

k1 = association constant

k2 = dissociation constant

k1 / k2 = AFFINITY


Types of Agonists/Antagonists

This diagram highlights the possible site for antagonist binding:



This diagram shows different types of antagonist binding and their effect on the agonist binding:



Let's take a look at a graphic representation of several types of binding and the outcomes of the overall therapeutic effect: 



Let's now look at a comparative diagram of full versus partial agonists: 



In this diagram we will look at the effect spare receptors can have on the effectiveness of an antagonist.


Self Check Questions: Pharmacodynamics

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Kinetic Overview

We just learned that kinetics is what our body does to the drug. This diagram illustrates possible paths for a drug after it is absorbed:


PH (ION) trapping can occur when an unionized drug crosses the membrane, but due to the conditions of the environment (PH) on the other side, the molecule becomes trapped. The amount of trapped drug is determined by the pKa (dissociation constant) of the drug and the PH of the environment (NSAIDs are a good example of this).

The following illustration shows how ionization can effectively trap molecules on one side of a membrane:



Let's take a look at how drugs are absorbed in the body...


Here is an example of two different drug formulations which have very different peaks:


Here we have two different drug formulas but the MEC (minimum effective concentration) is lower:


Let's look at a graph comparing IV dosing, oral dosing with 100% bioavailability, and oral dosing with 50% bioavailability:


Let's take a look at some examples of these:


Let's look at a graph of some different bioavailabilities:


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Let's take a look at a video clip of volume of distribution in the body:

This diagram shows how a drug molecule crosses cell membranes and the possible routes it may take through the body to get to its target site:


Let's take a closer look at protein binding in the following diagram:


Let's look at a graphic representation of this:


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Let's take a look at how drugs are metabolized by the body:


Let's take a look at a diagram of where renal secretion and reabsorption take place:


Let's take a look at how drugs are excreted by the body:

Please read the following journal article to help understand why we need to be concerned with kinetics from a clinical viewpoint. Click here to download the article.

Below is a comparison table of first order versus zero order drug concentrations remaining as time passes.


Half-LIfe (T 1/2)

Half-Life (T1/2) is the amount of time over which the drug concentration in the plasma decreases to ½ its original value. Because most drugs are eliminated by first order kinetics and the body can be considered a single compartment with a volume equal to that of the Vd, T1/2= 0.693xVd/clearance.

Therapeutic Dosing and Frequency

Therapeutic dosing goal is to maintain peak plasma concentration below the toxic concentration and the trough concentration above the minimum effective concentration (MEC). Steady State (SS) is reached after 4-5 half-lives for most drugs.


Does doubling the dose double the concentration?


Let's take a look at some examples of medication dosing:


Let's look at what effect different dosing methods could have:


Here we see what effect zero order (saturation kinetics) can have on dosing:



Possible outcomes of metabolism:




Here are some examples of Phase 1 (oxidative/reduction) metabolism by CYP 450



Here are some examples of Phase 2 metabolism (conjugation reaction)



Let's take a look at the first path effect and some ways to get around the problem:



Here is a diagram showing enzyme induction and inhibition of cyp450 enzymes:




Drug-Drug Interactions

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Drug Toxicity

Drug Toxicity Overview



Let's take a look at on-target and off-target effects:




Let's take a look at the 4 different types of harmful immune reactions:



Pathology of Drug Toxicity

Here is a diagram showing the mechanisms of action of drug toxicity:




Module 1 Case Studies

Case 1

Mr. W. is a 66-year-old technology consultant who makes frequent trips abroad as part of his job in the telecommunications industry. His only medical problem is chronic atrial fibrillation, and his only chronic medication is warfarin. Mr. W. flies to Turkey for a consulting job. On the last night of the trip, he attends a large dinner featuring shish kebabs and other foods he does not often eat. The next day, he develops profuse, watery, foul-smelling diarrhea. A physician makes a diagnosis of traveler's diarrhea and prescribes a 7-day course of trimethoprim–sulfamethoxazole.

Mr. W. feels entirely well 2 days into the course of antibiotics, and 4 days later (while still taking his antibiotics), he entertains some clients at another lavish dinner. Mr. W. and his guests become intoxicated at the dinner, and Mr. W. stumbles and falls on the curb as he is leaving the restaurant. The next day, Mr. W. has a markedly swollen right knee that requires evaluation in a local emergency department. Physical examination and imaging studies are consistent with a moderate-sized hemarthrosis of the right knee, and laboratory studies show a markedly elevated International Normalized Ratio (INR) which is a standardized measure of prothrombin time and, in this clinical setting, a surrogate marker for plasma warfarin level. The emergency physician advises Mr. W. that his warfarin level is in the supratherapeutic (toxic) range and that this effect is likely attributable to adverse drug–drug interactions involving warfarin, antibiotics, and recent alcohol intoxication.

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Case 2

You are working in a local clinic. Your patient, Mr. S, is a 65-year-old man who you have been following closely over the past few weeks for progressively elevated blood pressure readings. You have just confirmed blood pressure readings of 145/105 mm Hg in Mr. S. this morning. You decide to begin a thiazide diuretic and a beta-receptor antagonist as antihypertensive therapy. As you try to choose between atenolol and propranolol for Mr. S., you recall that the thiazide you will prescribe is 98% plasma protein bound in the blood. You also consider the following facts about the two beta-receptor antagonists.




Plasma protein binding



Urinary excretion of unchanged drug



Volume of distribution

39 L

270 L

β1/β2 selectivity

β1 selective


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