Drug Receptor Interactions and Cell Signaling- 5&6 Flashcards
What is a receptor?
any cellular macromolecule with which a drug interacts resulting in the change of one or more on-going cellular processes. Drugs do not initiate new processes. Responds to endogenous as well as exogenous substances. Usually coupled to an effector (transducer) or ion channel. Responsible for mediating the actions of many but not all classes of drugs.
Example: Epinephrine adrenergic receptors
alpha 1 subtype- constricts vascular smooth m.
beta 2 subtype- relaxes vascular smooth m.
-olol
beta blocker
Properties of receptors
a cell can only respond to a drug if it has the receptor for that drug. Receptors, like any other protein, undergo synthesis and degradation with variable lifespans. Receptors on a cell can be altered by diseases or chronic drug treatment, source of concern.
“Down regulation”
Excessive receptor stimulation leading to decreased receptor density.
“Up regulation”
Decreased receptor stimulation leading to increased receptor density.
Is drug binding reversible?
most drug-receptor binding is readily reversible. Binding and unbinding of the drug receptor complex is very fast
Types of binding
ionic, hydrophobic, ect.
Strength of the interaction determines the concentration of the drug required to interact with the receptor (binding affinity). Stronger interaction -> lower concentration required -> higher affinity.
Drug- receptor interactions exhibit…
Saturable response, reversibility, good potency, chemical selectivity, competitive blockade by antagonists, amplified responses.
4 receptor categories
Ion channels.
Guanine Nucleotide Binding Protein (G protein)- Coupled Receptors (GPCR).
Receptor Tyrosine Kinases (TRK).
Intracellular Receptors.
Ion channels and GPCR are common therapeutic targets
G protein coupled receptors
adrenergic, cholinergic, dopaminergic, histamine, opiate, serotonergic.
Ion channel coupled receptors
Nicotinic receptor gated Na+ channels, GABA- receptor gated Cl- channels, Glutamate (NMDA)- coupled cation channels.
Receptor ligands
ligands are small molecules that interact with or bind to a cellular macromolecule (receptor). Receptor ligands, aka drugs, are classified by the nature of the response they produce.
Two main types: Agonists and Antagonists.
Agonists
Full- 100% stimulation.
Partial- 1-99% stimulation.
Antagonists
Competitive- No stimulation, reversible.
Non competitve- No stimulation, irreversible.
Properties of receptor agonists
bind very rapidly to target receptors. After dissociating from receptor, the response dissipates quickly. Prolonged stimulation of receptors can lead to a diminished response. Produce changes that are independent of other ligands. A full agonist produces a complete or maximal effect. Sigmoidal dose-response plot.
Common receptor agonists
alpha 2 adrenergic: xylazine, detomidine, medetomidine.
alpha 1 adrenergic: phenylephrine.
beta 1/2 adrenergic: isoproterenol.
opiate receptors: morphine, fentanyl, butorphanol.
beta 1 receptors: dobutamine.
mucscarinic cholinergic: bethanecol.
beta 2 adrenergic: terbutaline
Properties of antagonists
drugs that bind to a receptor and block or prevent the action of a agonist. Zero efficacy. Bind and unbind from receptor slower than agonists. may be reversible or irreversible. Pure anatgonists are unable to elicit cellular action when given alone.
3 major types- competitive, noncompetitive, irreversible.
Competitive antagonists
antagonists that bind reversibly to a receptor. Binding happens at same site agonist would. They two are mutually competitive. One drug can override the other when present in excess.
A low concentration of competitive antagonist yields a modest parallel rightward shift.
Non-competitive antagonists
antagonists that bind irreversibly or bind to an alternate site of the receptor- agonists do not compete. Extent of receptor blockade is fixed and related to the dose of antagonist administered. Blockade cannot be overcome.
Dissociation constant (Kd)
a mathematical relationship that predicts the relative concentration of the drug-receptor complex at any concentration of drug.
Kd = K-1/K1 = DR/D.
Is independent from any cellular response and therefore can be determined for both agonists and antagnists.
Kd is the drug concentration at which half of the receptors are occupied by drug.
Practical relevance of Kd
indicates the relative drug concentration that is required in order for a drug to bind to a receptor. No relationship with efficacy. But measure of drug affinity.
High affinity= low Kd.
Low affinity= high Kd.
Potency
dose of drug needed to produce a desired level of effect.
High affinity doesn’t equal high potency.
Affinity
drug concentration required to occupy a target receptor.
High potency doesn’t equal high affinity.
Specificity
a measure of a drug’s ability to produce one effect (desireble) relative to its ability to produce another effect (undesirable).
Specificity= ED50 (undesirable)/ ED50 (desirable).
where ED50 is the dose that produces that effect in 50% of the target.
If ED of undesirable is greater than desirable that drug has good specificity. If it is about or equal it has poor specificity.
Measure of drug
most commonly determined by comparing drug doses that produce a desired effect relative to doses that are lethal. Can exhibit substantial species variation.
Therapeutic Index (TI)
a quantal response (yes or no) that is measured at the 50percent level.
TI= LD50/ED50
Margin of safety (MOS)
more stringent measure of drug safety. Avoids problems associated with non-parallel dose relationships for efficacy and lethality dose-response relationships.
MOS= LD1/ED99.
