Pharmacodynamics

Chapter 2 Pharmacodynamics



I. Definitions

A. Pharmacodynamics

• Involves the biochemical and physiologic effects of drugs on the body.

B. Receptor

• A macromolecule to which a drug binds to bring about a response.


Receptor is site that drug binds to, producing its actions.


C. Agonist

• A drug that activates a receptor upon binding.

D. Pharmacological antagonist

• A drug that binds without activating its receptor and, thus, prevents activation by an agonist.

E. Competitive antagonist

• A pharmacological antagonist that binds reversibly to a receptor so it can be overcome by increasing agonist concentration.

F. Irreversible antagonist

• A pharmacological antagonist that cannot be overcome by increasing agonist concentration.


Be able to distinguish reversible from irreversible binding drugs by how they affect log dose-response curves of an agonist (shown later in chapter).


G. Partial agonist

• A drug that binds to a receptor but produces a smaller effect at full dosage than a full agonist.


Be able to distinguish a full agonist from a partial agonists from log dose-response curves (shown later in chapter).


H. Graded dose-response curve

• A graph of increasing response to increasing doses of a drug.

I. Quantal dose-response curve

• A graph of the fraction of a population that gives a specified response at progressively increasing drug doses.


Understand the difference between a graded and quantal log dose-response curve (shown later in chapter).


II. Dose-Response Relationships

A. Overview

• These relationships are usually expressed as a log dose-response (LDR) curve.

B. Properties of LDR curves

1. LDR curves are typically S-shaped.

2. A steep slope in the midportion of the “S” indicates that a small increase in dosage will produce a large increase in response.

3. Types of log dose-response curves


a. Graded response (Fig. 2-1)


(1) Response in one subject or test system

image

2-1 Log dose-response curve for an agonist-induced response. The median effective concentration (EC50) is the concentration that results in a 50% maximal response.



Graded response is in an individual subject.


(2) Median effective concentration (EC50)

• Concentration that corresponds to 50% of the maximal response

b. All-or-none (quantal) response (Fig. 2-2)


(1) Number of individuals within a group responding to a given dose

image

2-2 A, Cumulative frequency distribution and frequency distribution curves for a drug using a logarithmic dose scale. B, Cumulative frequency distribution curves for the therapeutic and lethal effects of a drug using a logarithmic dose scale.



Quantal (all-or-none) response is in a population of subjects.


(2) The end point is set, and an individual is either a responder or a nonresponder

(3) This response is expressed as a normal histogram or cumulative distribution profile

(4) The normal histogram is usually bell-shaped


Graded response measures degree of change; quantal measures frequency of response.


(5) Median effective dose (ED50)

• Dose to which 50% of subjects respond

(6) The therapeutic index (TI) and the margin of safety (MS) are based on quantal responses.

(a) TI (therapeutic index): ratio of the lethal dose in 50% of the population (LD50) divided by the effective dose for 50% of the population (ED50), or image


TI = LD50 ÷ ED50


(b) MS (margin of safety): ratio of the lethal dose for 1% of the population (LD1) divided by the effective dose for 99% of the population (LD99), or


MS = LD1 ÷ ED99


III. Drug Receptors

• Drug receptors are biologic components on the surface of or within cells that bind with drugs, resulting in molecular changes that produce a certain response.

A. Types of receptors and their signaling mechanisms (Table 2-1)

1. Membrane receptors are coupled with a G protein, an ion channel, or an enzyme.


a. G protein-coupled receptors (GPCRs) (Table 2-2)


(1) These receptors are a superfamily of diverse guanosine triphosphate (GTP)-binding proteins that couple to “serpentine” (seven) transmembrane receptors.


TABLE 2-1 Drug Receptors and Mechanisms of Signal Transduction

image

TABLE 2-2 Major G Protein Signaling Pathways



















Gα Type Function* Coupled Receptors
Gs Stimulates adenylyl cyclase (↑ cAMP) Dopamine (D1), epinephrine (β1, β2), glucagon, histamine (H2), vasopressin (V2)
Gi Inhibits adenylyl cyclase (↓ cAMP) Dopamine (D2), epinephrine (α2)
Gq Stimulates phospholipase C (↑ IP3, DAG) Angiotensin II, epinephrine (α1), oxytocin, vasopressin (V1), Histamine (H1)

cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol triphosphate.


* In some signaling pathways, Gs and Gi are associated with ion channels, which open or close in response to hormone binding.


(Adapted from Pelley JW and Goljan EF: Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, Table 3-3.)




GPCRs; Gs stimulates cAMP; Gi inhibits cAMP; Gq stimulates phospholipase C.


(2) Gs-coupled receptors (Fig. 2-3)

(a) The Gsα subunits are coupled to adenylyl cyclase

(b) Activation stimulates the formation of intracellular cyclic adenosine monophosphate (cAMP)

(c) cAMP is responsible for numerous cellular responses (Table 2-3).

(d) cAMP activates protein kinase A

image

2-3 Cyclic adenosine monophosphate (cAMP) pathway. Following hormone binding, coupled G protein exchanges bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Active Gsα-GTP diffuses in the membrane and binds to membrane-bound adenylyl cyclase, stimulating it to produce cAMP. Binding of cAMP to the regulatory subunits (R) of protein kinase A releases the active catalytic (C) subunits, which mediate various cellular responses.


(From Pelley JW and Goljan EF: Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, Figure 3-6.)


TABLE 2-3 Effects of Elevated cyclic adenoside monphosphate (cAMP) in Various Tissues















































Tissue/Cell Type Hormone Increasing cAMP Major Cellular Response
Adipose tissue Epinephrine ↑ Hydrolysis of triglycerides
Adrenal cortex Adrenocorticotropic hormone (ACTH) Hormone secretion
Cardiac muscle Epinephrine, norepinephrine ↑ Contraction rate
Intestinal mucosa Vasoactive intestinal peptide, epinephrine Secretion of water and electrolytes
Kidney tubules Vasopressin (V2 receptor) Resorption of water
Liver Glucagon, epinephrine
↑ Glycogen degradation

↑ Glucose synthesis
Platelets Prostacyclin (PGI2) Inhibition of aggregation
Skeletal muscle Epinephrine ↑ Glycogen degradation
Smooth muscle (bronchial and vascular) Epinephrine
Relaxation (bronchial)

Vasodilation (arterioles)
Thyroid gland Thyroid-stimulating hormone Synthesis and secretion of thyroxine

(Adapted from Pelley JW and Goljan EF: Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, Table 3-4.)



cAMP activates protein kinase A.


(3) Gi-coupled receptors

(a) The Giα subunits are coupled to adenylyl cyclase

(b) Activation inhibits the formation of intracellular cyclic AMP (cAMP)

(c) Whereas the Giβγ subunits open K+ channels

(4) Gq-coupled receptors (Fig. 2-4)

(a) The Gqα subunits stimulate phospholipase C

(b) It cleaves PIP2 (phosphatidyl inositol 4,5-bisphosphate) to yield two second messengers

• IP3 (inositol 1,4,5-triphosphate), which can diffuse in the cytosol and release calcium from the endoplasmic reticulum

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Pharmacodynamics

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