1. PHARMACOLOGY INTRODUCTION
Lecture Three

2. Pharmacodynamics

3. Pharmacodynamics Is what the drug does to the body.
Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs.
Drug-Receptor Interactions
Binding
Dose-Response
Effect
Signal Transduction
Mechanism of action, Pathways

4. The Pharmacodynamic Phase
Describes the biochemical and physiologic action and effects of drugs in the body.
This phase occurs when the medication reaches the target cell, tissue, organ and a therapeutic effect occurs.

5. Mechanism of drug action
Physical and chemical mechanisms-
alter of the environment of the cell through either physical or chemical processes that usually do not affect cell function.
Drug Receptor Interactions-
Medications are thought to have an affinity for certain receptor sites.
Receptor sites- is the reactive site of a cell or tissue that can be occupied by a drug and result in a pharmacologic response.

7. Mechanism of Drug action cont. Types of receptors

8. Mechanism of Drug action cont. Types of receptors

9. Mechanism of action-Agonists, antagonists and partial agonisits.
Endogenous regulators within the body that occupy receptors elicit either
Agonist action-which activates receptor functions.
Antagonist actions-which prevents receptor functions

10. Mechanism of action-Agonists, antagonists and partial agonisits.
Endogenous regulators within the body that occupy receptors elicit either
Agonist action-which activates receptor functions or
Antagonist actions-which prevents receptor functions
When a drug acts like an
Agonist-it complexes with and alters the functional properties of the receptor(eg. Terbutaline)
Antagonist- it inhibitis or prevents the action of a natural agonist either through competition for the receptor site(eg. Antihistamine), or interaction with other components of the effector mechanisms(insecticides)
Antagonists can also block the actions of other drugs(eg. Narcan).

11. Agonists and Antagonists
A drug is said to be an agonist when it binds to a receptor and causes a response or effect.
It has intrinsic activity = 1
- - -
+ + +
+ + +
+ + -
- - -
+ - -
Depolarization

12. Agonists and Antagonists
A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has NO activity.
Its intrinsic activity is = 0

13. Agonists and Antagonists
PARTIAL AGONIST
A drug is said to be a partial agonist when it binds to a receptor and causes a partial response.
It has intrinsic activity < 1.

14. Agonists and Antagonists
PHARMACOLOGICAL ANTAGONISTS
Competitive
They compete for the binding site
Non-competitive
Bind elsewhere in the receptor (Channel Blockers).

15. Agonists and Antagonists
FUNCTIONAL ANTAGONISTS
Physiologic Antagonists
Chemical Antagonist

16. Agonists and Antagonists
Physiologic ANTAGONIST
A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest.
Its intrinsic activity is = 1, but on another receptor.
Glucocorticoid Hormones  Blood Sugar
Insulin  Blood Sugar

17. Agonists and Antagonists
Chemical ANTAGONIST
A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor.
A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur).
Heparin, an anticoagulant, acidic
If there is too much  bleeding and haemorrhaging
Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.

18. Drug Effect
Drug effects- can be immediate or delayed, desired or undesired, or unusual such as idiosyncratic.
The degree to which a drug produces a pharmacologic response or effect is determined by:
the availability of receptor sites
the location and function of receptors with which the drug interacts
the kind of drug action on target cells, tissues or organs
the concentration of the drug at the receptor sites

19. Drug effects cont. Dose-Effect relationships-
commonly derived from the drug’s peak effect after a single dose of the medication
Dose-Response Relationships-
the slope of the dose-response curve demonstrates the ability of the drug to produce an effect. The steeper the curve the more readily the drug binds with receptors and the quicker the drug effect
Efficacy of a drug refers to the drugs maximal effect
Potency of a drug is the relationship between the dose of the drug and the intensity of its effect.
Potency is influenced by absorption, distribution, biotransformation, excretion, and ability to combine with receptors.

20. Drug Effect cont.
Selectivity-refers to the effects that the medication precipitates-medications rarely produce a single effect, most produce multiple effects
Drug selectivity is best described by discussing the pattern and incidence of adverse ant toxic effects that are produced by a therapeutic dose of the medication. The proportion of clients who had to lower the dosage or discontinue the medication because of these effects is also summarized.
Therapeutic dose-produces the desired effect
non-therapeutic dose-too high or too low-will not
Therapeutic index-describes the relative safety of a drug. A drugs therapeutic index is equal to the lethal dose divided by the effective dose.

21. SEMILOG DOSE-RESPONSE CURVE
Effect or
Drug Concentration

22. SEMILOG DOSE-RESPONSE CURVE
ED50
50% Effect
Maximal Effect
Effect or
Response
Drug Concentration

23. SEMILOG DOSE-RESPONSE CURVE
EFFECT
POTENCY
EFFICACY
ED50
Maximal Effect
Log [Dose]

24. SEMILOG DOSE-RESPONSE CURVEA B C D
EFFECT
Log [Dose]
RANK ORDER OF POTENCY: A > B > C > D

25. SEMILOG DOSE-RESPONSE CURVEA B C D
RESPONSE
ED50
RANK ORDER OF POTENCY: A > B > C > D
RANK ORDER OF EFFICACY: A = C > B > D

26. Agonists and Antagonists
1. COMPETITIVE ANTAGONIST
Reversible & Surmountable
The effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with a
fraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect.

27. Agonists and Antagonists
RECEPTOR RESERVE OR SPARE RECEPTORS.
Maximal effect does not require occupation of all receptors by agonist.
Low concentrations of competitive irreversible antagonists may bind to receptors and a maximal response can still be achieved.
The actual number of receptors may exceed the number of effector molecules available.

28. Agonists and Antagonists
1. COMPETITIVE ANTAGONIST
Irreversible & Non-surmountable
The effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors.

29. Agonists and Antagonists
Synergism
The combined effect of two drugs is higher than the sum of their individual effects.
Additivity
The combined effect of two drugs is equal to the sum of their individual effects.

30. Therapeutic Index
Toxic effect

31. Therapeutic index Therapeutic Index = TxD50 ED50
As long as the slopes of the curves are similar, however, if not similar, we use the Standard Margin of safety:
Standard Margin of safety = TxD1–1 x 100
ED99
Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population.

32. Therapeutic Index
ED99
Toxic effect
ED1
ED13

33. Effects of Interactions
Additive
Effect of the drug combination is expected based on the sum of the doses of the 2 drugs
Synergistic
Effect of 1 drug is enhanced by another so the combined effect is greater than expected based on the sum of the doses of the 2 drugs
Antagonistic
One drug reduces the effectiveness of another
Additive is predictable.

34. Pharmacodynamics Variation in drug responsiveness
Individuals may vary considerably in their responsiveness to a drug
Idiosyncratic drug response – unusual, one that is infrequently observed in most patients
Caused by:
Genetic differences in metabolism
Immunologic mechanism (allergy)
tolerance

35. Variation in drug responsiveness
Hyporeactive – intensity of effect is decreased
Hyperreactive – intensity of effect is increased
Hypersensitivity – allergic or other immunologic response to drugs resulting from previous sensitizing exposure
Tolerance – responsiveness usually decreases as a consequence of continued drug administration.
Need greater doses of a drug to produce original degree of effect as time progresses or need to substitute different drug
Tachyphylaxis – responsiveness diminishes rapidly after administration of a drug (the first few doses), very rapid

36. Pharmacodynamics Variation in drug responsiveness Four general mechanisms:
1. Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood which may alter the conc of drug that reaches receptor
This can be due to age, weight, sex, disease state, liver and kidney function, and genetic differences

37. Pharmacodynamics
2. Patients may vary in their concentrations of endogenous receptor ligand
Can vary in the response to pharmacologic antagonist
Ex: Propranolol (β blocker)
Pt with pheochromocytoma opposed to healthy runner

38. Pharmacodynamics Variation in drug responsiveness
Four mechanisms (cont.)
3. Patients may have differences in the # of receptor sites or differ in the function of their receptors due to the efficiency of coupling receptor to effector
Drug Induced down-regulation
The “overshoot” phenomena
Antagonists – when discontinued, the elevated # of receptors can produce an exagerated response to physiologic conc of agonist
Agonist – when discontinued, # of receptors that have been dec by down regulation is too low for endogenous agonist to produce effective stimulation
Ex: Clonidine (α agonist) decreases blood pressure. When withdrawn, can produce hypertensive crisis. Pt will have to be weaned slowly
4. Patients vary in functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems
Can be caused by age of pt or general health of pt. Most importantly, severity and pathophysiologic mechanism of the disease
Drug therapy will be most successful when there is correct diagnosis and if it is accurately directed at the pathophysiologic mechanism responsible for the disease

39. Why Do We Study Pharmacology?
A. It’s good for you
B. You will be able to use fancy terms like ’bioavailabilty’
C. My instructor likes torture
D. A competent dentist must understand why his/her patient is getting a medication, and HOW IT WORKS