Understanding Drug Receptors and Actions

Posted on Jul 22, 2025 in Biotechnology

Receptors: Drug Interaction Sites

Receptors are macromolecules, present either on the cell surface, cytoplasm, or in the nucleus, where drugs bind and interact to produce cellular changes. Receptors are mostly proteins.

Classification of Receptors

Receptors are classified into the following types:

  • G-Protein Coupled Receptors
  • Ion Channel Receptors
  • JAK-STAT Binding Receptors
  • Enzymatic Receptors
  • Nuclear Receptors

G-Protein Coupled Receptors (GPCRs)

GPCRs are a large family of cell membrane receptors crucial for cellular signal transduction. They are present on the cell membrane surface and are also known as Metabotropic Receptors, Heptahelical Receptors, and Serpentine Receptors.

  • G-Proteins are membrane proteins with three subunits (α, β, γ) called heterotrimeric, along with GDP.
  • G-Proteins act as signal transducers.
  • GPCRs function via second messenger activation.
  • Second messengers include cAMP, IP3, DAG, and cGMP.
  • When a ligand binds to GPCR, it activates either Adenyl Cyclase or Phospholipase to generate respective second messengers.

Types of G-Proteins

  • Gs: Adenyl Cyclase Activation (cAMP ↑)
  • Gi: Adenyl Cyclase Inhibition (cAMP ↓)
  • Go: Ca2+ Channel Inhibition
  • Gq: Phospholipase C Activation (IP3 ↑, DAG ↑)

GPCRs control cell function through three major pathways:

  • Adenyl Cyclase-cAMP Pathway
  • Phospholipase C: IP3-DAG Pathway
  • Channel Regulation

Adenyl Cyclase (AC): cAMP Pathway

This pathway is activated by Gs and inhibited by Gi. Activation of Adenyl Cyclase increases the synthesis and intracellular accumulation of cAMP. cAMP acts through Protein Kinase, which phosphorylates and alters the function of many enzymes, ion channels, and structural proteins.

Pathway: Activation of AC → cAMP ↑ → Protein Kinase Activation → Phosphorylation of Proteins (enzymes, ion channels, structural proteins)

Functions:

  • Heart Contractility ↑
  • Smooth Muscle Relaxation
  • Liver (Glycogenolysis)
  • Adipose Tissue (Lipolysis)

Ion Channel Regulation

G-Protein activation can open and close specific ion channels without involving second messengers. Examples include:

  • Opening: β1 Adrenergic (B1)
  • Closing: α2 Adrenergic (α2), Muscarinic (M2)

Ion Channel Receptors

These are also known as Ligand-Gated Ion Channels or Ionotropic Receptors.

Enzymatic Receptors

These receptors are directly linked to tyrosine kinase. The receptor binding domain is present on the extracellular site, while the intracellular site possesses enzymatic activity.

Examples: Prolactin, Insulin, Growth Hormones, Cytokines.

Nuclear Receptors

These receptors are the slowest acting. Only lipid-soluble drugs can interact with them. When drugs bind to nuclear receptors, they subsequently bind to DNA, affecting translation, transcription, etc.

Two major types:

  • Cytoplasmic Receptors
  • Nuclear Receptors

JAK-STAT Binding Receptors

The JAK-STAT (Janus Kinase – Signal Transducer and Activator of Transcription) signaling pathway transmits information from external chemical signals, leading to DNA transcription and cellular activity. It consists of three main components:

  1. Receptor
  2. JAK
  3. STAT

Pathway of JAK-STAT Receptor

  1. Signaling Molecule Attaches to JAK-STAT Receptor
  2. Activated JAK → Phosphorylation of Tyrosine Residues
  3. Addition of STAT → Phosphorylation of STAT by JAK
  4. Dimerization of STAT → Cellular Responses

Factors Affecting Drug Action

Factors affecting drug action can be broadly categorized into:

  1. Physiological Factors
  2. Pharmacokinetic Factors
  3. Drug-Related Factors
  4. Environmental Factors

Physiological Factors

  • Age: Babies and young children have immature organs, processing drugs slowly. Older adults may have weaker liver and kidney function, prolonging drug presence and increasing side effect risk.
  • Gender: Men and women process drugs differently due to hormones, body fat, and muscle composition.
  • Body Weight: Heavier individuals may require higher doses. Fat-soluble drugs may persist longer in individuals with more body fat.
  • Genetics: Some individuals naturally metabolize drugs faster.

Pharmacokinetic Factors

These include absorption, distribution, metabolism, and excretion.

Adverse Drug Reactions (ADRs)

ADRs are harmful or unintended responses to a medication occurring at normal doses used for treatment, diagnosis, or prevention. Reactions can range from mild (nausea, rash) to severe (organ damage, life-threatening allergic reactions).

Types of Adverse Drug Reactions

  • Type A (Augmented): Common, predictable, dose-related, caused by the drug’s known pharmacological effects (e.g., bleeding from warfarin, hypoglycemia from insulin).
  • Type B (Bizarre): Less common, unpredictable, not dose-related, often due to allergies or genetic variations (e.g., anaphylaxis from penicillin).
  • Type C (Chronic): Associated with long-term drug use (e.g., adrenal suppression with long-term corticosteroids).
  • Type D (Delayed): Appear after some time, even after stopping the drug (e.g., cancer caused by chemotherapy drugs).
  • Type E (End of Use): Occurs when a drug is suddenly stopped (withdrawal) (e.g., seizures after stopping benzodiazepines).
  • Type F (Failure): Lack of drug effectiveness, often due to drug interactions or incorrect dosing (e.g., antibiotic resistance).

Pharmacovigilance

Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or other drug-related problems. Its primary goal is to improve patient safety and maximize therapeutic effects. This involves monitoring and analyzing data from various sources, including clinical trials and post-marketing reports, to identify and manage potential medication risks.

New Drug Development

From synthesis/identification to marketing, a new drug takes at least 10-20 years and is very costly. The stages include:

  1. Synthesis/Isolation of Compounds
  2. Pre-Clinical Trials
  3. Permission for Clinical Trials
  4. Pharmaceutical Formulation, Standardization of Chemicals
  5. Clinical Trials (Phase I, II, III)
  6. Review & Grant of Marketing Permission
  7. Post-Marketing Surveillance (Phase IV)

Pre-Clinical Trials

These are the initial testing phases before human trials. They involve:

  • Laboratory Research: Experiments using cell cultures or tissue samples to investigate biological effects and mechanisms, identifying potential benefits and risks.
  • Animal Testing: Assessing safety, efficacy, and pharmacokinetics in animals to evaluate harmful side effects and determine appropriate dosages.

Clinical Trials

Clinical trials are research studies conducted with human participants to evaluate the safety, efficacy, and potential side effects of new drugs, treatments, or medical services.

Phases of Clinical Trials

Clinical trials consist of five phases:

  1. Phase 0 (Microdosing): Early stage to gather preliminary data on drug behavior in the human body, performed in a very small group of participants.
  2. Phase 1: Evaluates drug safety and determines metabolic and pharmacodynamic effects. Performed in 20-100 healthy individuals.
  3. Phase 2: Focuses on establishing therapeutic efficacy and evaluating the drug’s dose range. Performed in 100-300 patients with the target disease. Duration: 6 months to several years.
  4. Phase 3: Focuses on safety, tolerability, and possible drug interactions on a wider scale. It’s a therapeutic confirmatory trial performed in hundreds to thousands of patients. Duration: 3-5 years.
  5. Phase 4 (Post-Marketing Surveillance): Ongoing monitoring and assessment after the drug is approved and available to the public, focusing on long-term effects and overall impact.