drug receptor interaction (c) mrunal


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What is drug receptor interaction? : 

Drugs or ligand binds with receptor and mediate their Pharmacological action What is drug receptor interaction?

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Drug act via the interaction with four kind of regulatory proteins Enzymes (e.g inhibition of dihydrofolate reductase by trimethoprim). Carriers(eg.prozac inhibits serotonin transporter). Ion channels(eg.local anaesthetics inhibit Na+ channels). Receptor proteins(eg. The antiallergic zyrtec blocks the histamine H1 receptor).

What is a receptor? : 

The term “receptor” specifically refers to proteins that participate in intracellular communication via chemical signals. Receptors mediate the action of agonist and antagonist. Receptors are responsible for the selectivity of drug action. Receptors determine the quantitative relationship between drug dose and pharmacological effect. What is a receptor?

How do they work? : 

How do they work?

Chemistry of Receptors and Ligands : 

Interaction of receptors with ligands involves the formation of chemical bonds, most commonly electrostatic and hydrogen bonds, as well as weak interactions involving van der Waals forces. The bonds are usually reversible, except that covalently bond. e.g. of irreversible bond aspirin, anti tumor drug. Chemistry of Receptors and Ligands

Major Receptor Families : 

Ligand-gated ion channels G protein–coupled receptors Enzyme-linked receptors Intracellular receptors Major Receptor Families

G protein–coupled receptors : 

G protein–coupled receptors Structure: Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices There’s a G protein attached to the cytoplasmic side of the membrane

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Three subunits, an α subunit that binds guanosine triphosphate (GTP). And the β , γ subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel. These effectors are known as second messangers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes.

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G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate and diacylglycerol. These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well. This family of receptors transduces signals derived from odors, light, and numerous neurotransmitters, including norepinephrine, dopa-mine, serotonin, and acetylcholine.

Ligand-gated ion channels : 

Ligand-gated ion channels Structure: Protein pores in the plasma membrane That are responsible for regulation of the flow of ions across cell membranes. The activity of these channels is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid, having durations of a few milliseconds. The nicotinic receptor and the γ-aminobutyric acid (GABA) receptor are important examples of ligand-gated receptors.

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Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. Although not ligand-gated, ion channels, such as the voltage-gated sodium channel, are important drug receptors for several drug classes, including local anesthetics.

Enzyme-linked receptors : 

Enzyme-linked receptors Structure: Receptors exist as individual polypeptides Each has an extracellular signal-binding site An intracellular tail with a number of tyrosines and a single å helix spanning the membrane.

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Upon activation the receptoris activated and is able to Phosphorylate Tyrosine residues of other intracellular proteins. Protein phosphorylation is one of the underlying mechanisam Of the regulation of protein function.

Intracellular receptors : 

Not all signal receptors are located on the plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. The signal molecule must be able to pass through plasma membrane. Examples: ~Nitric oxide (NO) ~Steroid (e.g., estradiol, progesterone, testosterone) Intracellular receptors

Drugs : 

Agonist Antagonist Drugs

Agonist : 

Agonist means the drugs interact with and activate receptors; they possess both affinity and efficacy. Affinity means the ability of drug to combine with the receptor and form the drug receptor complex. Efficacy means the ability of drug to initiate the effect. The affinity of the agonist can be determine by finding out the PD2 value. Agonist

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two types Full – an agonist with maximal efficacy Partial – an agonist with less then maximal efficacy

Antagonist : 

Antagonists interact with the receptor but do not change the receptor they have affinity but not efficacy two types Competitive Noncompetitive Antagonist

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Competative Antagonist binds with the same receptor as the agonist Antagonist resembles chemically with the agonist Parallel rightward shift of agonist DRC. The same maximal response can be attained by increasing dose of agonist. Intensity of response depends on concentration of both agonist & antagonist. E.g. Ach-atropine, morphine-naloxone. Binds to another site of receptor Does not resemble Flattening of agonist DRC. Maximum response is suppressed. Response depends only on the concentration of antagonist E.g. papaverine -acetylcholine, dizepam-bicuculline Noncompetative

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Competative Noncompetative

Lock & key model of drug receptor interaction : 

Lock & key model of drug receptor interaction If the drug causes the receptor to respond in the same way as the naturally occuring substance, then the drug is reffered to as an agonist. Other drug work in opposite way as antagonist,these drug bind to the receptor ,but do not produce a responds.

Dose respons relationships : 

Graded dose–response relationships Quantal dose–response relationships Dose respons relationships

Graded dose–response relationships : 

The response is a graded effect, meaning that the response is continuous and gradual. Infinite number of intermediate states. E.g. Vessel dilation, blood pressure change, heart rate changes etc. Curve indicates maximum efficacy of the drug in individual. Two important properties of drugs can be determined by graded dose–response curves. Potency Efficacy Graded dose–response relationships

Potency : 

Potency A measure of the amount of drug necessary to produce an effect of a given magnitude. Ec 50 is used to determine potency. Drug A is more potent as compare to Drug B.

Efficacy : 

Efficacy The ability of a drug to illicit a physiologic response when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses. Efficacy is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent

Quantal dose–response relationships : 

Quantal dose–response relationships Response is all or non phenomenon E.g. death, pregnancy, cure,pain relief. Quantal dose–response curves are useful for determining doses to which most of the population responds. Curve indicates variability in responses among the people. Information regarding the margin of safety of a drug.

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