PHARMACOLOGICAL BIOCHEMISTRY:  DRUG-RECEPTOR INTERACTIONS & PHARMACOKINETICS

Drug-receptor interactions refer to the binding of drugs to receptors, which can be either inside the cell or on the cell membrane. The interaction of a drug with a particular receptor is described by the terms affinity, potency, and efficacy. Drug-receptor interactions can be classified into agonists, antagonists, and partial agonists. The drug-receptor interaction is essentially an exchange of the hydrogen bond between a drug molecule, surrounding water, and the receptor site.

Table of Content:

  1. Drug-Receptor Interaction
  2. Mechanisms of drug binding to receptors
  3. Types of drug receptors (e.g., G-protein coupled receptors, enzyme receptors)
  4. Agonists, antagonists, and allosteric modulators
  5. Pharmacokinetics
  6. Absorption Kinetics
  7. Types of Pharmacokinetics Models
  8. Drug Distribution: Absorption, Drug metabolism, Bioavailability, Half-life, drug excretion
  9. Conclusion

 

1. Drug-Receptor Interactions:

Drug-receptor interactions refer to the binding of drugs to specific receptors in the body, which can lead to a biological response. The following are salient points about drug-receptor interactions:

 

Mechanisms of drug binding to receptors

- Ligands bind to precise molecular regions, called recognition sites, on receptor macromolecules.

- The binding site for a drug may be the same as or different from that of an endogenous agonist (hormone or neurotransmitter).

- Drugs can interact with receptors by activating the agonist binding site, competing with the agonist, or acting at separate allosteric sites.

 

TYPES OF DRUG RECEPTORS

Drug receptors are specific proteins or molecular structures in the body that interact with drugs, hormones, or neurotransmitters to initiate a biological response. These interactions are crucial for the effectiveness of many drugs. There are several types of drug receptors, each with its unique characteristics and mechanisms of action. The following are some of the main types of drug receptors:

 

1. G Protein-Coupled Receptors (GPCRs):

   - GPCRs are one of the largest and most diverse families of drug receptors.

   - They are located in the cell membrane and are involved in signal transduction.

   - Ligand binding to a GPCR activates a signaling cascade through G proteins, leading to various cellular responses.

   - Examples include adrenergic receptors, dopamine receptors, and serotonin receptors.

 

2. Ion Channel Receptors:

   - Ion channel receptors are integral membrane proteins that regulate the flow of ions (e.g., Na+, K+, Ca2+) across the cell membrane.

   - Ligand binding to these receptors can either open or close the ion channel, thereby affecting the cell's electrical activity.

   - Examples include nicotinic acetylcholine receptors and glutamate receptors.

 

3. Enzyme-Linked Receptors:

   - These receptors have intrinsic enzymatic activity or are associated with enzymes.

   - Ligand binding to these receptors activates their enzymatic function, leading to intracellular signaling events.

   - Examples include receptor tyrosine kinases (e.g., insulin receptor) and guanylate cyclase receptors.

 

4. Nuclear Receptors:

   - Nuclear receptors are located in the cell nucleus and regulate gene expression.

   - They typically bind lipophilic ligands, such as steroid hormones (e.g., estrogen, testosterone).

   - Activation of nuclear receptors can result in changes in gene transcription and protein synthesis.

 

5. Tyrosine Kinase Receptors:

   - These receptors have intrinsic kinase activity.

   - Binding of ligands leads to receptor dimerization and autophosphorylation, initiating intracellular signaling pathways.

   - Examples include the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR).

 

6. Serine/Threonine Kinase Receptors:

   - Similar to tyrosine kinase receptors but phosphorylate serine and threonine residues.

   - Transforming growth factor-beta (TGF-β) receptors are a well-known example.

 

7. Ligand-Gated Ion Channels:

   - These receptors are membrane proteins that form ion channels.

   - Ligand binding causes a conformational change, leading to the opening or closing of the ion channel.

   - Examples include the acetylcholine receptor at neuromuscular junctions and the gamma-aminobutyric acid (GABA) receptor.

 

8. Cytokine Receptors:

   - These receptors are involved in the immune response and respond to various cytokines.

   - Binding of cytokines to their receptors triggers intracellular signaling pathways.

   - Examples include interleukin receptors and interferon receptors.

 

9. Pattern Recognition Receptors (PRRs):

   - PRRs are part of the innate immune system and recognize pathogen-associated molecular patterns (PAMPs).

   - They play a crucial role in initiating immune responses against infections.

   - Examples include Toll-like receptors (TLRs).

 

AGONISTS, ANTAGONISTS, AND ALLOSTERIC MODULATORS

- Agonists are drugs that bind to a receptor and cause a biological response. Full agonists can generate a maximal response at a receptor, while partial agonists are only able to generate a fraction of the possible response at a receptor.

- Inverse agonists bind to a receptor and cause a decrease in signaling at that receptor.

- Antagonists bind to receptors without causing their activation, and compete with endogenous ligands for receptor binding.

- Allosteric modulators may display special pharmacological properties not shared by orthosteric ligands. They may potentiate or reduce potency and/or efficacy of orthosteric ligands, without intrinsic activity of their own. They may achieve these by allosterically modulating the affinity and/or functional efficacy of another ligand.

 

 

 PHARMACOKINETICS:

   - Drug absorption, distribution, metabolism, and elimination (ADME)

   - Bioavailability and half-life

   - Drug-drug interactions

 

 

Pharmacokinetics is the study of how the body interacts with administered substances for the entire duration of exposure. It is closely related to but distinctly different from pharmacodynamics, which examines the drug’s effect on the body more closely. Pharmacokinetics involves four main parameters: absorption, distribution, metabolism, and excretion (ADME). These parameters determine the onset, duration, and intensity of a drug’s effect.

 

DRUG ABSORPTION: Drug absorption is a crucial pharmacokinetic process that involves the movement of a drug from its site of administration into the bloodstream. The rate and extent of drug absorption can significantly impact the drug's effectiveness, onset of action, and potential for side effects. The key aspects of drug absorption includes:

 

1. Routes of Administration:

   - Drugs can be administered through various routes, including:

     - Oral: The drug is taken by mouth, usually in the form of tablets, capsules, liquids, or suspensions. Oral administration is convenient and often preferred, but it can be affected by factors such as gastric acidity, food, and first-pass metabolism in the liver.

     - Intravenous (IV): The drug is injected directly into the bloodstream. This route provides rapid and complete drug absorption, making it ideal for emergencies and situations where precise control of drug levels is necessary.

     - Intramuscular (IM) and Subcutaneous (SC): Drugs are injected into muscle or under the skin, respectively. Absorption is generally slower than IV administration but faster than oral administration.

     - Topical: Drugs are applied directly to the skin or mucous membranes, often for localized effects. Absorption can vary widely depending on the drug's formulation and the thickness of the skin.

     - Inhalation: Drugs are inhaled into the lungs, allowing for rapid absorption due to the extensive surface area and rich blood supply in the lungs.

 

FACTORS AFFECTING DRUG ABSORPTION

Several factors can influence the rate and extent of drug absorption in the body. These factors includes:

     - Formulation: The drug's physical form (e.g., tablets, capsules, solutions) and the presence of excipients can impact its dissolution and absorption.

     - Solubility: Water-soluble drugs are generally absorbed more rapidly than poorly water-soluble drugs.

     - pH: Gastric pH can affect the solubility and stability of certain drugs, particularly in the case of oral administration.

     - Food: Taking a drug with or without food can affect its absorption. Some drugs are better absorbed when taken with a meal, while others should be taken on an empty stomach.

     -First-Pass Metabolism: Orally administered drugs pass through the liver before entering the systemic circulation, where they may undergo metabolism. This can significantly reduce their bioavailability.

     -Blood Flow: The blood supply to the site of administration can influence absorption. Well-vascularized tissues generally promote faster absorption.

     - Drug Interactions: Co-administration of other drugs may influence the absorption of a drug through various mechanisms.

 

Absorption Kinetics:

 Drug absorption is often described using pharmacokinetic models. Pharmacokinetic models are used to describe, analyze, and interpret data obtained during in vivo drug disposition studies. These models are used to determine various pharmacokinetic parameters such as volume of distribution, half-life, area under the curve, and absorption rate constant. There are two major approaches to pharmacokinetic modeling: model-dependent and model-independent. Model-dependent approaches are also called compartmental models, which divide the body into compartments and describe the drug's movement between them. One of the most common compartmental models is the one-compartment open model.

 

 

Types of Pharmacokinetic Models:

 

One Compartment Open Model: One Compartment Open Model: This model assumes that the drug is distributed uniformly throughout the body and that the elimination of the drug follows first-order kinetics. The model is based on the assumption that the drug is administered intravenously as a bolus. The model has a single compartment that represents the entire body, and the drug is eliminated from the body through the kidneys. The model is simple and easy to use, but it does not account for the complexities of drug distribution and elimination.

 

 

Two Compartment Open Model: Pharmacokinetic two-compartment model divided the body into central and peripheral compartment. The central compartment (compartment 1) consists of the plasma and tissues where the distribution of the drug is practically instantaneous. The peripheral compartment (compartment 2) consists of tissues where the distribution of the drug is slower.

Other types of compartmental models include the three-compartment model, and whole-body PBPK models. Each model has its own benefits and drawbacks, and the choice of model depends on the drug's properties and the research question.

 

Figure *** . Two-compartment model with first-order absorption and elimination. AGI, A1, and A2 are the amounts of drug in gastrointestinal tract (GI), central compartment (including plasma), and peripheral compartment, respectively. ka, k12, k21, and k10 represent the first-order fractional rate constants for absorption, distribution, redistribution, and elimination.

 

In summary, drug absorption describes how the drug moves from the site of administration to the site of action. To reach its target tissue, a drug must enter the systemic circulation, which includes being introduced directly into the blood (intravenous or intra-arterial administration), absorbed through the skin, and though the digestive system. It is a complex process that can vary depending on the route of administration, the drug's properties, and individual patient factors. Understanding these factors is crucial for healthcare professionals to optimize drug therapy, choose the most appropriate administration route, and ensure that patients receive the desired therapeutic effects.

 

DRUG DISTRIBUTION: This describes the journey of the drug through the bloodstream to various tissues of the body. The drug can be distributed to different organs and tissues, and its concentration can vary depending on factors such as blood flow, tissue binding, and the drug's chemical properties.

 

DRUG METABOLISM: Drug metabolism describes the process that breaks down the drug. The liver is the primary site of drug metabolism, where enzymes convert the drug into metabolites that can be excreted from the body.

 

DRUG EXCRETION: This describes the elimination of the drug from the body. The kidneys are the primary site of drug excretion, where the drug and its metabolites are filtered from the blood and excreted in the urine.

 

BIOAVAILABILITY: Bioavailability is a critical concept related to drug absorption. It represents the fraction of the administered dose that reaches the systemic circulation unchanged and is available to produce its therapeutic effects. IV administration typically results in 100% bioavailability, while other routes may have lower bioavailability due to factors like incomplete absorption or first-pass metabolism.

 

 

HALF-LIFE: This is the time it takes for the concentration of a drug in the body to decrease by half. It is an important parameter in determining the dosing interval of a drug.

 

DRUG-DRUG INTERACTIONS: This occurs when the presence of one drug affects the pharmacokinetics of another drug. This can lead to changes in drug concentration, efficacy, and toxicity.

 

CONCLUSION

Drug-receptor interactions are essential in pharmacology as they determine the efficacy and safety of drugs. A receptor is a protein molecule that binds to a ligand, which can be an endogenous neurotransmitter/hormone or an external pharmacological agent (drug). The binding of a ligand to a receptor can result in a cellular response. The interaction of a drug with a particular receptor is described by the terms affinity, potency, and efficacy.

Affinity: This is the probability of the drug occupying a receptor at any given instant. It is related to the drug's chemical structure.

Potency: This is the amount of drug required to produce a given effect. It is related to the drug's affinity and intrinsic efficacy.

Efficacy: This is the degree to which a ligand activates receptors and leads to a cellular response. It is related to the drug's intrinsic activity.

A drug's ability to affect a given receptor is determined by its affinity and intrinsic efficacy. A drug can activate or inactivate a receptor, and activation can increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes, and few drugs are absolutely specific for one receptor or subtype.

The drug-receptor interaction is essentially an exchange of the hydrogen bond between a drug molecule, surrounding water, and the receptor site. The vast majority of drugs show a remarkably high correlation of structure and specificity to produce pharmacological effects. Experimental evidence indicates that drugs interact with receptor sites. Since many drugs contain acid or amine functional groups that are ionized at physiological pH, ionic bonds are formed by the attraction of opposite charges in the receptor site. Polar-polar interactions, as in hydrogen bonding, are a further extension of the attraction of opposite charges.

 

 

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