Introduction

PHARMACOLOGY INTRODUCTION

Lecture Three

Pharmacodynamics

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

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.

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.

Mechanism of Drug action cont.Types of receptors

Mechanism of Drug action cont.Types of receptors

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

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).

Agonists and Antagonists

AGONIST 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

Agonists and Antagonists

ANTAGONIST 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


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.

Agonists and Antagonists

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

Agonists and Antagonists

FUNCTIONAL ANTAGONISTS Physiologic Antagonists Chemical Antagonist

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 SugarInsulin  Blood Sugar

Agonists and Antagonists

Chemical ANTAGONISTA 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, acidicIf there is too much  bleeding and haemorrhagingProtamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.

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

Drug effects cont.

Dose-Effect relationships-commonly derived from the drug’s peak effect after a single dose of the medicationDose-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 effectEfficacy of a drug refers to the drugs maximal effectPotency 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.


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.

Drug Concentration

Response
SEMILOG DOSE-RESPONSE CURVE
Effect or

Drug Concentration

Response
SEMILOG DOSE-RESPONSE CURVE
ED50
50% Effect
Maximal Effect
Effect or

SEMILOG DOSE-RESPONSE CURVE

EFFECT
POTENCY
EFFICACY
ED50
Maximal Effect
Log [Dose]

SEMILOG DOSE-RESPONSE CURVE

RANK ORDER OF POTENCY: A > B > C > D
A
B
C
D
EFFECT
Log [Dose]

SEMILOG DOSE-RESPONSE CURVE

RANK ORDER OF POTENCY: A > B > C > D RANK ORDER OF EFFICACY: A = C > B > D
A
B
C
D
RESPONSE
ED50



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.

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.

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.

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.

Therapeutic Index

Toxic effect

Therapeutic index

Therapeutic Index = TxD50 ED50As 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 ED99Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population.


Therapeutic Index
Toxic effect
ED99
ED13
ED1

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

Pharmacodynamics Variation in drug responsiveness

Individuals may vary considerably in their responsiveness to a drugIdiosyncratic drug response – unusual, one that is infrequently observed in most patientsCaused by:Genetic differences in metabolismImmunologic mechanism (allergy)tolerance

Variation in drug responsiveness

Hyporeactive – intensity of effect is decreasedHyperreactive – intensity of effect is increasedHypersensitivity – allergic or other immunologic response to drugs resulting from previous sensitizing exposureTolerance – 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 drugTachyphylaxis – responsiveness diminishes rapidly after administration of a drug (the first few doses), very rapid

PharmacodynamicsVariation in drug responsivenessFour 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



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

Pharmacodynamics

Variation in drug responsivenessFour 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 effectorDrug Induced down-regulationThe “overshoot” phenomenaAntagonists – when discontinued, the elevated # of receptors can produce an exagerated response to physiologic conc of agonistAgonist – when discontinued, # of receptors that have been dec by down regulation is too low for endogenous agonist to produce effective stimulationEx: Clonidine (α agonist) decreases blood pressure. When withdrawn, can produce hypertensive crisis. Pt will have to be weaned slowly4. Patients vary in functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systemsCan be caused by age of pt or general health of pt. Most importantly, severity and pathophysiologic mechanism of the diseaseDrug therapy will be most successful when there is correct diagnosis and if it is accurately directed at the pathophysiologic mechanism responsible for the disease

Why Do We Study Pharmacology?

A. It’s good for youB. You will be able to use fancy terms like ’bioavailabilty’C. My instructor likes tortureD. A competent dentist must understand why his/her patient is getting a medication, and HOW IT WORKS