1. Module II The Basics of the Brain, the Body and Drug Actions
Segment B
General Principles of Drug Actions – The Foundation of Drug Actions in the CNS
Kim Edward Light, Ph.D.
Professor, College of Pharmacy
University of Arkansas for Medical Sciences

2. Objectives
Identify the various perspectives for understanding drug actions.
Describe the pharmaceutical and pharmacokinetic phases of drug actions.
Describe the pharmacodynamic, therapeutic, and toxic phases of drug actions.
Identify ADME and the important aspects of each.
List the major routes of drug administration and elimination.
Identify the role of distribution and biotransformation in drug actions.
What is the importance of dose-response relationships in drug action?

3. Objectives
Identify the difference between quantal and graded dose-responses.
Differentiate between potency and efficacy in regards to drug actions?
Define agonists, antagonists, partial agonists and how their presence in combination impacts the resulting drug effects.
Identify the difference between competitive and non-competitive antagonist drug actions.
Identify the importance of signal transduction and how the type of receptor determines the transduction process.

4. Aspects of Drug Actions
Pharmaceutical
Pharmacokinetic
Pharmacodynamic
Therapeutic
Toxic

5. Pharmaceutical aspects
Drug absorption.
Routes of administration
Oral
Injection (iv, im, ia)
Topical
Inhalation
Rectal
Pharmaceutical aspects include the processes and actions necessary to prepare the drug for absorption into the body. These aspects include the route of drug administration and the processes necessary to control its dissolution and absorption into the blood stream. as well as to stabilize the drug in the preparation so that it maintains its potency “on the shelf.”

6. Pharmacokinetic Aspects
Distribution
Absorption
ADME
Metabolism
Biotransformation
This involves the delivery and maintenance of drug concentrations to the physiological sites of activity. Involves four processes including: Absorption - Distribution - Metabolism or Biotransformation - and - Elimination (ADME).
Elimination

7. Absorption TRANSDERMAL CAPSULE AEROSOL SUB-LINGUAL TABLET SYRUP IV IM
The processes that result in the drugs entry into circulatory system. Important considerations are dosage forms - tablet, suppository, aerosol, injectables, sub-lingual, syrup, liquid, patch preparations. Sustained or extended release preparations include microencapsulation (“tiny little time pellets”), slow-release intramuscular preparations, and transdermal patches.
SUB-LINGUAL
TABLET
SYRUP IV IM
SUPPOSITORY

8. Distribution Delivery of the drug to tissues Apparent “barriers”
Blood flow
Most drugs “like” fat (lipophilic)
Plasma protein binding
Apparent “barriers”
Blood-Brain Barrier
Synovial barrier
Placental Barrier
Breast milk
Common type of drug-drug interaction - Two drugs having high degree of plasma protein binding results in displacement and increased side-effects. Since the body’s cells are composed of fat-based membranes the ability of the drug to cross membranes is an important and often limiting factor.
Most drugs cross membranes and penetrate into tissues by a process called Passive Diffusion – that is they move from a region of higher concentration to a region of lower concentration. To move drugs or neurotransmitters against a concentration such as the transmitter reuptake process requires energy and is called Active Transport.
Finally, there are several apparent barriers in the body that serve to restrict (but not prevent) penetration by various drugs. The most well known is the Blood-Brain Barrier that limits the ability of some drugs from having actions in the brain. Other barriers that limit drug penetration are the Synovial barrier that protects the various joints of the body and the placental and breast milk barriers. In reality, very few drugs are found that do not readily cross the placenta into the fetus or are secreted into Breast milk.

9. Metabolism Biotransformation
To render the drug more water-soluble
Liver, GI tract, lungs, kidneys, brain
Cytochrome P450 (CYP) / mixed function oxidases
Split molecular O2 to oxidize drug
The purpose of metabolism or as it is more commonly referred to recently biotransformation is to make the drug more water soluble and thus more easily eliminated in the urine. In the process we find that many drugs are converted to inactive metabolites. Some drugs are converted to metabolites that retain pharmacological activity and some drugs are actually converted from inactive to active pharmacological agents by metabolism. In this later case we call the original drug a prodrug and we can take advantage of this metabolic process to increase the targeting of drug therapy.
The tissue sites where most of drug metabolism or biotransformation occurs include the Liver, GI tract, lungs, kidneys, and brain. It should be no surprise that the liver and GI tract – and to some extent the lungs - are well equipped to alter foreign compounds since they are often the primary routes of drug entry into the body. Although there are many approaches utilized by the body for accomplishing this task the most significant family of enzymes for drug metabolism are the Cytochrome P450 family also known as the Mixed Function Oxidases. This family of enzymes operates in a manner similar to the plant based photosynthesis process as they split a molecule of Oxygen (O2) and attach one oxygen atom to the drug and the other is used to make water.
X + O X-O + H2O
CYP + 2NADPH
CYP + 2NADP+

10. Metabolism Biotransformation
Specialized forms of CYP enzymes
CYP3A4 >50% of drugs
CYP2D6 many CNS and cardiovascular drugs
Other enzyme systems:
alcohol dehydrogenase
plasma esterase enzymes
Many specialized forms of Cytochrome P450 exist that show selectivity for various classes of drugs, i.e. CYP3A4 >50% of drugs; CYP2D6 acts on many CNS and cardiovascular drugs, and CYP2C9, CYP1A2 and numerous others are important. Scientists are discovering that genetic based differences in these different CYP drug metabolizing enzymes account for the reasons some drugs work better in some people than in others. In the not so distant future it may be that an individual patients profile of CYP enzymes may be conducted before prescribing drug therapy in order to select the drug most likely to have a beneficial effect with fewer side effects.
There are other enzyme systems in the body that are capable of metabolizing some drugs. Alcohol dehydrogenase is the primary means for metabolizing alcohol and plasma esterase enzymes are responsible for metabolizing cocaine.

11. Elimination or Excretion
Filtration by the kidneys
Eliminated in urine
Some passed into the bile
After liver metabolism
Other important routes:
breath,
sweat,
saliva,
milk,
hair,
finger/toe nails
The two primary means of elimination are the renal (kidney) and hepatic (liver) mechanisms. Drugs and drug metabolites are filtered in the kidneys by a mechanism that results in the elimination of drugs and metabolites in the urine.

12. Time Course of Drug Actions
Plasma Concentration
Graphical representations of drug actions are critical and when the time course of drug in plasma is reviewed the four kinetic areas of ADME can be visualized.

13. Pharmacokinetic Terminology
Clearance
the total time to completely eliminate the drug from the body
Half-life (T½)
the amount of time for the concentration to decrease by half
Important terms used to express the time required to remove the drug from the body. Clearance represents the total time to completely eliminate the drug while the half-life is the time to decrease the concentration by half. Often times people get confused about half-life.

14. Half-Lives For example, for a drug with an T½ of 6 hours
@ 0 hours = 100 mg/ml in the plasma
@ 6 hours = 50 mg/ml
@ 12 hours = 25 mg/ml
Note: each T½ decreases the previous concentration by half
This type of elimination is called FIRST-ORDER since the amount of drug eliminated per unit time is dependent on one variable – concentration
One half-life
Two half-lives
Three half-lives
Four half-lives
Five half-lives
Here is an example. A certain drug has a half-life of 6 hours. If at time 0 the concentration was 100 mg/ml then after one half-life the concentration would be 50 mg/ml. Now what would the concentration be after another half-life of 6 hours??? The answer is 25 mg/ml. I bet many of you were thinking that another 50 mg/ml would be eliminated in the second half-life.
Here is another illustration that might be helpful. Think about having a length of rope that you cut it in half and discard one piece. At the end of one “half-life” the length of rope is shorter. Now you cut the remaining piece in half and discard one piece. The length of rope is now ¼ that of the original. You again cut the rope in half and discard a piece and then again and again. You have now passed through 5 “half-lives” and the remaining length of rope is only 1/32 of the original. Thus 3.1% of the rope remains and 96.9% has been eliminated in 5 half-lives.

15. Pharmacodynamics Dose-Response Relationships Two perspectives
Drug actions are related to dose
More drug = more actions
Two perspectives
response of a population of subjects to a given drug (i.e. how many respond)
The response magnitude (or graded response)
Now we turn our attention to the area of pharmacodynamics. This aspect of drug action is concerned with the alterations to the physiological system that the drug mediates and how those alterations result in therapeutic or toxic effects. The most fundamental aspect of pharmacodynamics is the concept of the relationship between Dose and Response. Intuitively it should make sense that it will require some minimal amount of drug to be present before any response or effect is noticed. Likewise, it should follow that if more drug is added then more response or effect is the result. Finally, it may be implied that there must be some limit to the ability to respond to a drug since the physiological system is clearly limited.
In considering dose-response relationships and drug effects there are two perspectives that are important. If you are treating a group of people with a drug and measuring a specific effect (say sleeping) then you are studying the responsiveness of a population of people to the production of a specific “all-or-none” response – sleeping.

16. Dose Responses in Populations
Relates the number (or %) of subjects that respond in a specific manner (i.e. sleep).
Large numbers of individuals increases accuracy.
Clinical trials in new drug testing
If tested population is too small or not diverse then the results will not be translatable to all individuals.
This perspective is termed Population Based or Quantal Response relationships. Clearly as you give more drug then more people in the group will respond and ultimately you will achieve a dose where 100% of the population has responded. Those who respond to lower doses may be more sensitive to the drug effects and those who require larger doses to respond may be more resistant to the drug effects. The critical aspect of this perspective is a response that is “all or none” termed a quantal response. Studies employing this perspective are represented by the clinical trials of drug evaluation testing and the recommended dose for treatment of specific effects are based on this type of perspective.
These doses are termed Therapeutic Doses. There are also Toxic or Lethal Doses and these are (hopefully) higher than the dose to produce a therapeutic effect. Sometimes we will develop a general measure of a dose to produce a given level of response in 50% of a population. Most of you have probably heard mention of an LD50 and this refers to the dose of a drug that will cause lethality (dead) in 50% of a population.

17. Graded Dose Responses Dose that produces 50% of Maximal Response
Another perspective for dose-response relationships is the magnitude of a particular response produced by various doses of the drug in a single individual or averaged across many individuals. Low doses should produce very small responses while increasing the dose should produce more and more of the response until a dose is reached that produces all the response the system has to offer. If we take the example of heart rate increases giving certain drugs (such as caffeine) will increase heart rate. If we give higher doses we get greater increases in heart rate until the heart is beating so fast that even giving higher doses can not make the heart beat faster. This viewpoint is a focus on the magnitude of a response and is different from the other viewpoint. Both perspectives are important to our discussions about drug effects and the various pharmacodynamic parameters that impact drug effects.

18. Receptor Drug Interactions
Affinity
How well the receptor and drug are attracted to each other
Efficacy
How much response is produced by drug-receptor interaction
Potency
Comparative measure of how much drug is required to produce a certain magnitude of response
In our discussions of drug actions its important to identify several definitions or terminology that are used to describe drug actions. Three important aspects of drug actions are the – affinity, efficacy, and potency.

19. Graded Dose Responses Types of drug actions
Agonist = bind and produce a response
Affinity and efficacy (Drug A or B)
Antagonist = bind but don’t produce response (block agonist, however)
Affinity but no efficacy (Drug D)
Partial Agonist = bind and produce weak response
Affinity and weak efficacy (Drug C)
Next we need to discuss three terms that describe the types of effects or alterations that result from drug administration. Some drugs have both affinity for a receptor and efficacy – that is an ability to initiate a response. Thus they may mimic the responses of the neurotransmitter that normally attaches to the receptor. These drugs are called AGONISTS. Alternatively some drugs have affinity but no efficacy. They thus are able to bind to the receptor but they are not able to stimulate a response. Nevertheless, their occupation of the receptor prevents the normal neurotransmitter from being able to bind to the receptor so these drugs are called “blockers” or ANTAGONISTS. Since antagonists do not produce a response their effect is only evident if there is a concentration of the normal neurotransmitter present. In that case the response to the neurotransmitter (or agonist) is reduced and more is required to get an equal response to the response when the antagonist was absent.
Finally there are some drugs that have affinity and efficacy but the amount of efficacy is less than the normal agonist. These drugs are called PARTIAL AGONISTS. Their effects will mimic the agonist if there is no agonist present, however, they will look like Antagonists if there are concentrations of agonist present.

20. Understanding Drug Actions
A fundamental principle of pharmacology is that drugs do not produce effects that are new or novel to the physiological system.
Drugs act within the physiological system to alter responses
How drug actions are produced is essentially a question of how physiological systems are designed.

21. Drug Mechanisms Agonist
direct = a drug that binds to and activates specific receptors
affinity and efficacy
indirect = a drug that results in an increase in the presence and ability of the endogenous transmitter’s binding to the receptor

22. Drug Mechanisms Antagonist
direct = a drug that binds to but does not activate specific receptors
Affinity no efficacy
indirect = a drug that results in a decrease in the presence or ability of the transmitter to bind with the receptor

23. Drug Mechanisms Partial Agonist Affinity and weak efficacy
Therefore, it may sometimes act as an agonist or antagonist.
If no agonist is present, then partial agonist produces some response.
If agonist and partial agonist are present then less agonist can bind so total response is less – like antagonist

24. Pharmacodynamic Principles
Tolerance
the ability of the body to adapt to the presence of a drug that alters physiological functioning.
subsequent exposure will require higher doses to produce the same magnitude of response

25. Pharmacodynamic Principles
Withdrawal
adverse physiological symptoms produced by the absence of a drug
physiological alterations to oppose drug actions
removal of the drug results in the expression of the physiological alterations

26. Pharmacodynamic Principles
Dependence
physiological state characterized by the presence of adverse signs and symptoms that occur when the drug or treatment is withdrawn.

27. Pharmacodynamic Principles
withdrawal
adaptation
Homeostasis (balance)
drug
adaptation
dependence
drug
Drug effects to alter the system
System responds to oppose drug effects (tolerance)
Absence of drug results in expression of the system’s adaptations (withdrawal)
Drug presence is necessary to balance the system’s adaptations (dependence)

28. Summary Perspectives of drug actions ADME Dose-response relationships
Pharmaceutics, kinetics, dynamics, etc.
ADME
Dose-response relationships
Drug Actions
agonists, partial agonists, antagonists
Pharmacodynamic principles
(affinity, efficacy, tolerance, dependance, etc.)