💊Intro to Pharmacology Unit 2 – Drug-Receptor Interactions in Pharmacodynamics

Key Concepts and Definitions

• Pharmacodynamics studies the biochemical and physiological effects of drugs on the body, focusing on the mechanisms of drug action and the relationship between drug concentration and effect
• Receptors are macromolecules (typically proteins) that drugs bind to, initiating a series of events leading to the drug's effects on the body
• Drug-receptor interactions involve the binding of a drug to its specific receptor, which can lead to changes in the receptor's conformation, activation of signaling pathways, and ultimately, the drug's pharmacological effects
• Affinity refers to the strength of the attraction between a drug and its receptor, with higher affinity indicating a stronger binding interaction
• Efficacy is the ability of a drug to produce a maximum response upon binding to its receptor, with higher efficacy resulting in a greater pharmacological effect
• Potency is a measure of the amount of drug required to produce a specific effect, with more potent drugs requiring lower doses to achieve the desired response
• Agonists are drugs that bind to receptors and activate them, producing a biological response
  • Full agonists can produce the maximum response a receptor is capable of
  • Partial agonists produce a lower maximum response compared to full agonists
• Antagonists are drugs that bind to receptors but do not activate them, blocking the effects of agonists and preventing the receptor from producing a biological response

Types of Drug-Receptor Interactions

• Lock-and-key model suggests that a drug (the key) fits precisely into the receptor (the lock), leading to the activation of the receptor and subsequent biological effects
• Induced-fit model proposes that the binding of a drug to its receptor causes a conformational change in the receptor, allowing for a better fit and leading to receptor activation
• Covalent binding occurs when a drug forms a strong, irreversible chemical bond with its receptor, leading to long-lasting effects that persist until the receptor is degraded or new receptors are synthesized
• Non-covalent interactions, such as hydrogen bonding, van der Waals forces, and electrostatic interactions, are weaker and reversible, allowing drugs to dissociate from their receptors over time
• Allosteric modulation involves the binding of a drug to a site on the receptor distinct from the primary binding site (the orthosteric site), leading to changes in receptor conformation and function
  • Positive allosteric modulators enhance the effects of agonists by increasing their affinity or efficacy
  • Negative allosteric modulators reduce the effects of agonists by decreasing their affinity or efficacy
• Competitive antagonism occurs when an antagonist competes with an agonist for the same binding site on the receptor, preventing the agonist from binding and producing its effects
• Non-competitive antagonism involves an antagonist binding to a different site on the receptor or to a separate subunit, reducing the efficacy of the agonist without affecting its binding to the primary site

Receptor Structure and Function

• Receptors are typically composed of one or more subunits, each with specific structural domains that contribute to the receptor's overall function
• Ligand-binding domains are regions of the receptor that specifically interact with drugs (ligands), leading to changes in receptor conformation and activation of signaling pathways
• Transmembrane domains are present in many receptors (e.g., G protein-coupled receptors) and span the cell membrane, allowing the receptor to communicate signals from the extracellular to the intracellular environment
• Intracellular domains often interact with downstream signaling molecules (e.g., G proteins, kinases) to propagate the signal initiated by drug binding
• Ion channels are receptors that, upon activation by a drug, allow the passage of specific ions (e.g., sodium, potassium, calcium) across the cell membrane, leading to changes in cellular excitability
• Enzyme-linked receptors possess intrinsic enzymatic activity (e.g., kinase activity) that is modulated by drug binding, leading to the activation or inhibition of downstream signaling cascades
• G protein-coupled receptors (GPCRs) are the largest family of receptors and are characterized by their interaction with intracellular G proteins upon drug binding, leading to the modulation of various signaling pathways

Binding Kinetics and Affinity

• Binding kinetics describe the rates at which drugs associate with (kon) and dissociate from (koff) their receptors, influencing the onset and duration of drug action
• Association rate (kon) is the rate at which a drug binds to its receptor, with faster association rates leading to a more rapid onset of drug effects
• Dissociation rate (koff) is the rate at which a drug dissociates from its receptor, with slower dissociation rates leading to a longer duration of drug effects
• Equilibrium dissociation constant (Kd) is the ratio of the dissociation rate to the association rate (Kd = koff/kon) and is a measure of the affinity of a drug for its receptor
  • Lower Kd values indicate higher affinity, as the drug is more likely to be bound to the receptor at equilibrium
  • Higher Kd values indicate lower affinity, as the drug is more likely to be unbound at equilibrium
• Residence time is the average time a drug remains bound to its receptor before dissociating, with longer residence times often associated with prolonged drug effects
• Binding cooperativity occurs when the binding of one ligand to a receptor influences the binding of subsequent ligands, either positively (positive cooperativity) or negatively (negative cooperativity)

Dose-Response Relationships

• Dose-response relationships describe the relationship between the dose of a drug and the magnitude of its pharmacological effect, often represented by dose-response curves
• Graded dose-response curves show a gradual increase in the drug effect with increasing doses, eventually reaching a plateau at the maximum effect (Emax)
• Quantal dose-response curves depict the percentage of a population responding to a drug at different doses, typically used to determine the median effective dose (ED50) or median lethal dose (LD50)
• Potency is often quantified using the EC50 (the concentration of a drug that produces 50% of its maximum effect) or the ED50 (the dose of a drug that produces a response in 50% of the population)
• Therapeutic index (TI) is the ratio of the median lethal dose (LD50) to the median effective dose (ED50) and represents the safety margin of a drug
  • A higher TI indicates a wider safety margin, as there is a larger difference between the dose that produces the desired effect and the dose that causes toxicity
  • A lower TI indicates a narrower safety margin, as the difference between the effective and toxic doses is smaller
• Receptor reserve refers to the concept that maximum drug effects can be achieved without occupying all available receptors, providing a buffer against fluctuations in drug concentration or receptor density

Agonists and Antagonists

• Agonists are drugs that bind to receptors and activate them, producing a biological response
  • Full agonists can produce the maximum response a receptor is capable of, occupying a high proportion of receptors at saturating concentrations
  • Partial agonists produce a lower maximum response compared to full agonists, even at saturating concentrations, as they have lower intrinsic efficacy
• Inverse agonists are drugs that bind to receptors and reduce their constitutive activity (basal activity in the absence of an agonist), producing effects opposite to those of agonists
• Antagonists are drugs that bind to receptors but do not activate them, blocking the effects of agonists and preventing the receptor from producing a biological response
  • Competitive antagonists compete with agonists for the same binding site on the receptor, and their effects can be overcome by increasing the concentration of the agonist
  • Non-competitive antagonists bind to different sites on the receptor or to separate subunits, reducing the efficacy of the agonist without affecting its binding to the primary site
• Mixed agonist-antagonists are drugs that display both agonist and antagonist properties, acting as agonists at some receptors and antagonists at others, or exhibiting different effects depending on the dose or tissue
• Biased agonists (or functionally selective agonists) are drugs that preferentially activate specific signaling pathways downstream of a receptor, potentially leading to more targeted therapeutic effects and fewer side effects

Signal Transduction Pathways

• Signal transduction pathways are the cellular mechanisms by which the binding of a drug to its receptor is translated into a biological response
• Second messengers are intracellular signaling molecules (e.g., cyclic AMP, calcium, inositol triphosphate) that are generated or released in response to receptor activation and amplify the signal
• G protein-coupled receptor (GPCR) signaling involves the activation of intracellular G proteins, which can modulate the activity of enzymes (e.g., adenylyl cyclase) or ion channels, leading to changes in second messenger levels or cellular excitability
• Receptor tyrosine kinase (RTK) signaling is initiated by the binding of growth factors to RTKs, leading to receptor dimerization, autophosphorylation, and the recruitment of downstream signaling molecules (e.g., Ras, MAPK)
• Jak-STAT signaling is activated by cytokine receptors, leading to the phosphorylation of STAT proteins, which then dimerize and translocate to the nucleus to regulate gene expression
• Phosphoinositide 3-kinase (PI3K) signaling is involved in various cellular processes, such as cell growth, survival, and metabolism, and is often dysregulated in cancer
• Crosstalk between signaling pathways allows for the integration of multiple signals and the fine-tuning of cellular responses, but can also contribute to the development of drug resistance or side effects

Clinical Applications and Examples

• Beta-adrenergic receptors are GPCRs targeted by drugs such as beta-blockers (e.g., propranolol) for the treatment of hypertension, angina, and anxiety
  • Beta-1 selective agonists (e.g., dobutamine) are used to increase cardiac output in patients with heart failure
  • Non-selective beta agonists (e.g., epinephrine) are used to treat anaphylaxis and cardiac arrest
• Opioid receptors (mu, delta, and kappa) are GPCRs targeted by opioid analgesics (e.g., morphine, fentanyl) for the treatment of pain
  • Naloxone, a competitive opioid receptor antagonist, is used to reverse opioid overdose
  • Buprenorphine, a partial agonist at mu opioid receptors, is used for the treatment of opioid addiction
• Serotonin (5-HT) receptors are targeted by various drugs, including antidepressants (e.g., SSRIs like fluoxetine), anti-emetics (e.g., 5-HT3 receptor antagonists like ondansetron), and antimigraine agents (e.g., triptans like sumatriptan)
• Dopamine receptors are involved in the pathophysiology of several neurological and psychiatric disorders, and are targeted by antipsychotics (e.g., haloperidol, a D2 receptor antagonist) and anti-Parkinson's drugs (e.g., levodopa, a dopamine precursor)
• Angiotensin II receptors (AT1) are targeted by angiotensin receptor blockers (ARBs, e.g., losartan) for the treatment of hypertension and heart failure
• Histamine receptors (H1 and H2) are targeted by antihistamines for the treatment of allergic reactions and gastric acid secretion, respectively
  • H1 receptor antagonists (e.g., diphenhydramine) are used to treat allergic rhinitis and urticaria
  • H2 receptor antagonists (e.g., ranitidine) are used to reduce gastric acid secretion in peptic ulcer disease and gastroesophageal reflux disease (GERD)