Lippincott’s pharmacology Chapter 2

describes what a drug does to the body and the influence of drug concentrations on the magnitude of the response

signal transduction
the process by which the drug-receptor complex initiates alteration in biochemical and/or molecular activity of a cell by a process called signal transduction

a small molecule that binds to a site on a receptor protein

second messenger molecules
part of the cascade of events tha translates ligand binding into a cellular response

Four families of ligands
1)ligand gated ion channels
2)G protein-coupled receptors
3)enzyme linked receptors
4)intracellular receptors

transmembrane ligand gated channels
rapid response
mediate diverse functions (e.g., neurotransmission, cardiac conduction, and muscle contraction).

Transmembrane G protein couple receptors
most abundant type of receptors
activation accounts for the actions of most therapeutic agents
stimulation results in responses that last several seconds to minutes
mediate neurotransmission, olfaction, and vision

a second messenger that regulates protein phosphorylation
activated by adenyl cyclase which is activated by alpha GTP subunits

phopholipase C
activated by G protein and activates inositol-1,4,5 triphosphate (IPsub3) and diacyglycerol (DAG)

second messenger responsible for the regulation of intracellular free calcium concentrations and of other proteins as well

second messenger that activates several enzymes such as protein kinase C (PKC) within the cell leading to a myriad or physiological effects

Enzyme Linked Receptors
protein that spans the membrane (dimer or multisubunit)
cytosolic enzyme activity
response is minutes to hours
most common type have tyrosine kinase activity
e.g. insulin receptors

Intracellular receptors
ligand must diffuse into cell
targets transcription factors->DNA -> RNA->various proteins
also targets structural proteins, enzymes, RNA, and ribosomes
observable response: 30-min or more; duration is hours to days
e.g. steroid hormones

Signal Transduction Features
The ability to amplify small signals
Mechanisms to protect the cell from excessive stimulation

Signal amplification
ligand-receptor complex can interact with many G proteins
activated G proteins persist for longer than original L-R complex (e.g., albuterol)
“Spare receptors” e.g., insulin (99% are spare)

Desensitization and Down regulation of receptors
receptors become desensitized
receptors may sequester within cell via endocytosis

when repeated administrations of a drug results in a diminished effect; receptors are present but unresponsive

the measure of the amount of drug necessary to produce an effect of a given magnitude;

The measurement used to determine potency

the ability of a drug to elicit a response when it interacts with a receptor
a drug greater efficacy is more beneficial than a drug with greater potency

what is efficacy dependent on?
The number of drug-receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses

assumptions of mathematical model that describes drug concentration and receptor binding
1. the magnitude of the response is proportional to the amount of receptors bound or occupied
2. The Esub-max occurs when all receptors are bound
3. binding of the drug to the receptor exhibits no cooperativity

Full agonists
two definitions
a drug that binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand
a drug that binds to a receptor, stabilizing the receptor in its active conformational state

Partial agonists
efficacy is less than a full agonist, even if all receptors are occupied
can act as an antagonist of a full agonist (e.g., aripiprozole)

Inverse agonists
stabilize the inactive R form
decrease the number of activated receptors to below that observed in the absence of drug

competitive antagonists
prevent an agonists from binding to its receptor and maintain receptor in its inactive conformational state (e.g., terozasin)
can be overcome by adding more agonist

Irreversible antagonists
causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present
cannot be overcome by adding more agonist

functional antagonism
antagonist acts at a completely separate receptor, initiating effects that are functionally opposite those of the agonist

chemical antagonism
prevents the actions of an agonist by modifying or sequestering the agonist so that it is incapable of binding to and activating its receptor

pharmacokinetic antagonism
antagonism effectively reduces the active drug concentration
can occur when absorption of drug is decreased or if metabolism and renal excretion are increased

therapeutic index (TI)
the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

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Non-catalytic Receptors Ligand or drug reversibly binds the receptor and elicits an effect; the ligand remains unaltered by the non-catalytic receptor Catalytic Receptors Ligans or drug reversibly binds the receptor and elicits an effect; the ligand is altered by the …

Regulatory proteins Best-characterized and most receptors, mediate endogenous chemical signals Enzymes Targeted for inhibition WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY FOR YOU FOR ONLY $13.90/PAGE Write my sample Transport proteins Na+/K+ ATPase receptor for cardiovascular …

what is pharmacology (pharmacology) study of actions of drugs or chemical substances on physiological process what is a drug (pharmacology) an agent that interacts with specific target molecules in the body and produces a physiological effect WE WILL WRITE A …

Slide 1: They are well known negative regulators of G-protein-coupled receptor (GPCR) signalling. We are going to review their classical functions and highlight some of the new discoveries that have been found. As there has been recent evidence to suggest …

EC50 the drug concentration giving 50% maximal effect (not binding affinity – the magnitude of a drug effect is not proportional to the proportion of receptors occupied by that drug) a drug with a lower EC50 is more potent (half …

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