PHCY 503: Drug Information

What is the disease relevant mechanism for conventional NSAIDs?

RA and OA can converge on increased COX-2-associated prostanoid production, nociceptor sensitization, and inflammatory pain.

What is the drug target, target family and location for conventional NSAIDs?

cyclooxygenase-2 enzyme (COX-2), cyclooxygenase enzymes, in inflammatory cells at sites of inflammation.

What is the target logic and baseline function of the drug target for conventional NSAIDs?

In inflammatory cells expressing increased COX-2, the enzyme catalyzes conversion of AA into PGG2 into PGH2 which is converted by downstream synthases to prostanoids but PGE2 contributes to inflammatory signaling and nociceptor sensitization.

What is the pharmacologic activity and mechanism of action for conventional NSAIDs?

reverisble competitive inhibitor, inhibits COX-2, decreasing PGH2 formation and downstream synthesis of PGE2 and other prostanoids.

What are the cellular and physiological effects of using conventional NSAIDs?

Reduced EP-receptor/prostanoid-dependent signaling and nociceptor sensitization in inflammatory tissue and other cells/tissues. Reduced inflammatory pain signaling.

What are the therapeutic effects of conventional NSAIDs?

analgesic, anti-inflammatory, anti-pyretic, improved function when inflammatory pain is reduced.

What are the adverse effects of the conventional NSAIDs?

GI injury/bleeding from COX-1 inhibition, renal injury/fluid retention, increased thrombotic CV risk

What is the disease relevant mechanism for systemic corticosteroids?

In RA and other inflammatory disorders, persistent or excessive immune activation and inflammatory signaling contribute to pain, swelling, and tissue injury.

What is the drug target, target family and location for systemic corticosteroids?

glucocorticoid receptors (GR), steroid hormone nuclear receptor, inflammatory and immune cells.

What is the target logic and baseline function of the drug target for systemic corticosteroids?

endogenous cortisol typically binds the GR, and activated receptor modulates gene expression involved in inflammatory/immune responses and broad metabolic and homeostatic physiology, pleiotropic.

What is the pharmacologic activity and mechanism of action for systemic corticosteroids?

agonist, activates GR inducing broad changes in gene transcription that increase anti-inflammatory activity and decrease pro-inflammatory activity.

What are the cellular and physiological effects of using systemic corticosteroids?

Broad changes in gene expression reduce pro-inflammatory cytokine and mediator production and immune-cell activation. Broad suppression of inflammatory and immune activity amongst metabolic, CV/fluid, bones, endocrine.

What are the therapeutic effects of systemic corticosteroids?

Reduced pain, swelling, and other manifestations of inflammatory disease.

What are the adverse effects of the systemic corticosteroids?

Immunesuppression/increased infection risk, hyperglycemia, HPA-axis suppression, osteoporosis

What is the disease relevant mechanism for DMARDs?

RA involves persistent immune-cell activation and synovial inflammation.

What is the pharmacologic activity and mechanism of action of DMARDs?

it is not defined but involves folate-dependent metabolic enzymes, endolysomal acidic compartments, and prodrug into 5-ASA

What is the drug target, target family and location for DMARDs?

not defined, synovial fibroblasts or immune cells relevant

What is the target logic and baseline function of the drug target for DMARDs?

the immunomodulation of these processes allows for broad reduction of immune inflammatory disease.

What are the cellular and physiological effects of using DMARDs?

reduced inflammatory and immune cell activation. reduced synovial inflammation.

What are the therapeutic effects of conventional DMARDs?

reduced RA signs/symptoms and disease activity.

What are the adverse effects of the DMARDs?

possible GI toxicity, hepatoxtoxicity, embryo-fetal toxicity, renal toxicity, hypersensitivty/rash

What is the disease relevant mechanism for JAK inhibitor targeted synthetic DMARDs?

In RA, persistent signaling by multiple cytokines through JAK-STAT pathways contributes to immune-cell activation, synovial inflammation, and tissue injury.

What is the drug target, target family and location for JAK inhibitor targeted synthetic DMARDs?

Janus kinase (JAK) enzymes, non-receptor protein tyrosine kinase, imune cells or synovial fibroblasts

What is the target logic and baseline function of the drug target for JAK inhibitor targeted synthetic DMARDs?

JAKs couple cytokine-receptor activation to STAT phosphorylation. Activated STATs regulate gene expression controlling immune-cell function and hematopoiesis.

What is the pharmacologic activity and mechanism of action for JAK inhibitor targeted synthetic DMARDs?

reversible competitive inhibitor, inhibits JAK kinase activity at the ATP-binding site, reducing STAT phosphorylation and activation downstream of multiple cytokine receptors.

What are the cellular and physiological effects of using JAK inhibitor targeted synthetic DMARDs?

Reduced STAT activation and cytokine-dependent gene transcription in immune cells. Reduced synovial and systemic inflammation; altered hematopoietic and host-defense function.

What are the therapeutic effects of JAK inhibitor targeted synthetic DMARDs?

Reduced RA disease activity and improved physical function.

What are the adverse effects of JAK inhibitor targeted synthetic DMARDs?

Serious infections (including herpes zoster) from impaired cytokine-dependent host defense; cytopenias from altered hematopoietic signaling; elevated lipid concentrations.

What is the disease relevant mechanism for SAMAs and LAMAs?

Cholinergic activation of bronchiolar smooth muscle contributes to bronchoconstriction and airflow limitation in COPD.

What is the drug target, target family and location for anti-inflammatory SAMAs and LAMAs?

muscarinic M3 acetylcholine receptor (M3), GPCR, bronchiolar SMC

What is the target logic and baseline function of the drug target for SAMAs and LAMAs?

ACh released by parasympathetic neurons activates M3 receptors on bronchiolar smooth muscle cells to maintain smooth muscle tone and regulate bronchiolar caliber. Receptor activation engages Gq-PLC-IP3-Ca²⁺ signaling to promote smooth muscle contraction.

What is the pharmacologic activity and mechanism of action for SAMAs and LAMAs?

reversible, orthosteric antagonists, blocks ACh binding to M3 receptors, reducing receptor activation.

What are the cellular and physiological effects of using SAMAs and LAMAs?

Reduced Gq-PLC-IP3-Ca²⁺ signaling and bronchiolar smooth muscle contraction. Bronchodilation and reduced airway resistance.

What are the therapeutic effects of SAMAs and LAMAs?

Improved airflow and reduced dyspnea and other respiratory symptoms.

What are the adverse effects of SAMAs and LAMAs?

Dry mouth; urinary retention; blurred vision from muscarinic blockade outside the airways.

What is the disease relevant mechanism for SABAs and LABAs?

Acute bronchiolar smooth muscle contraction contributes to bronchoconstriction and airflow limitation in asthma and other reversible obstructive airway disease.

What is the drug target, target family and location for SABAs and LABAs?

beta-2 adrenergic receptor, GPCR, bronchiolar SMC

What is the target logic and baseline function of the drug target for SABAs and LABAs?

Epi secreted by the adrenal medulla activates beta-2 AR on bronchiolar smooth muscle cells to help regulate bronchiolar caliber. Receptor activation engages Gs-adenylyl cyclase-cAMP-PKA signaling to promote smooth muscle relaxation.

What is the pharmacologic activity and mechanism of action for SABAs and LABAs?

agonist, activates beta-2 adrenergic receptors on bronchiolar SMC.

What are the cellular and physiological effects of using SABAs and LABAs?

Increased Gs-adenylyl cyclase-cAMP-PKA signaling and reduced bronchiolar smooth muscle contraction. Rapid bronchodilation and reduced airway resistance.

What are the therapeutic effects of SABAs and LABAs?

Rapid relief of bronchospasm; improved airflow and reduced wheezing and dyspnea.

What are the adverse effects of SABAs and LABAs?

Tremor; tachycardia/palpitations; hypokalemia with greater systemic beta-2 AR stimulation; receptor desensitization with excessive use.

What is the disease relevant mechanism for TNF blocking agents, DMARD?

Excess or persistent TNF signaling contributes to synovial inflammation and tissue injury in RA and other immune-mediated disorders.

What is the drug target, target family and location for TNF blocking agents, DMARD?

tumor necrosis factor (TNF), TNF superfamily cytokine, extracellular fluid; surfaces of TNF-producing immune or stromal cells

What is the target logic and baseline function of the drug target for TNF blocking agents, DMARD?

During inflammatory and immune responses, TNF binds TNFR1 and TNFR2 to activate signaling that promotes inflammatory gene expression, endothelial activation, leukocyte recruitment, and immune-cell activation.

What is the pharmacologic activity and mechanism of action for TNF blocking agents, DMARD?

neutralizing monoclonal antibody, binds TNF and prevents its interaction with TNFRs, reducing downstream inflammatory signaling.

What are the cellular and physiological effects of using TNF blocking agents, DMARD?

Reduced TNFR-dependent NF-κB/MAPK signaling; reduced pro-inflammatory cytokine production, endothelial activation, and leukocyte recruitment. Reduced synovial and systemic inflammation; reduced tissue-destructive signaling.

What are the therapeutic effects of TNF blocking agents, DMARD?

Reduced inflammatory disease activity and improved function; slowed structural joint damage in inflammatory arthritis.

What are the adverse effects of TNF blocking agents, DMARD?

Serious infections, including reactivation of latent infections, from impaired TNF-dependent host defense.

What is the disease relevant mechanism for interlukin-1 receptor antagonists?

Excess or persistent IL-1 signaling contributes to synovial inflammation, cartilage/bone injury, and systemic inflammation.

What is the drug target, target family and location for interlukin-1 receptor antagonists?

interlukin-1 type I receptor, interlukin-1 receptor family, immune cells or synovial fibroblasts and other stromal cells.

What is the target logic and baseline function of the drug target for interlukin-1 receptor antagonists?

During inflammatory and immune responses, IL-1α and IL-1β bind IL-1RI to activate signaling that promotes inflammatory gene expression, fever, leukocyte activation, cartilage degradation, and bone resorption.

What is the pharmacologic activity and mechanism of action of interlukin-1 receptor antagonists?

reversible orthosteric antagonist, competitively binds IL-1R1 and prevents IL-1a and IL-1b from activating and reducing downstream inflammatory signaling.

What are the cellular and physiological effects of interlukin-1 receptor antagonists?

Reduced IL-1RI-dependent NF-κB/MAPK signaling and pro-inflammatory gene expression. Reduced synovial and systemic inflammation; reduced cartilage/bone-destructive signaling.

What are the therapeutic effects of using interlukin-1 receptor antagonists?

Reduced IL-1-driven inflammatory disease activity and manifestations.

What are the adverse effects of using interlukin-1 receptor antagonists?

Serious infections from impaired IL-1-dependent host defense; neutropenia.

What is the disease relevant mechanism for interlukin-6 receptor antagonists?

Excess or persistent IL-6 signaling contributes to synovial inflammation, acute-phase responses, and systemic immune activation.

What is the drug target, target family and location for interlukin-6 receptor antagonists?

interlukin-6 receptors, interlukin type 1 cytokine receptors, immune cells or hepatocytes in the liver or soluble IL-6R in extracellular fluid

What is the target logic and baseline function of the drug target for interlukin-6 receptor antagonists?

During inflammatory and immune responses, IL-6 binds IL-6R and the gp130 signaling complex to activate JAK/STAT and other pathways that promote immune-cell activation, hepatic acute-phase protein synthesis, and hematopoietic responses.

What is the pharmacologic activity and mechanism of action of interlukin-6 receptor antagonists?

reversible orthosteric antagonists, binds soluble and membrane-bound IL-6R and reduced downstream signaling from IL-6 mediated receptor activation.

What are the cellular and physiological effects of interlukin-6 receptor antagonists?

Reduced JAK/STAT signaling and inflammatory/acute-phase gene expression. Reduced synovial and systemic inflammation; reduced hepatic acute-phase response.

What are the therapeutic effects of using interlukin-6 receptor antagonists?

Reduced inflammatory disease activity and systemic manifestations; slowed structural joint damage in RA.

What are the adverse effects of using interlukin-6 receptor antagonists?

Serious infections from impaired IL-6-dependent host defense; neutropenia; increased lipid concentrations.

What is the disease relevant mechanism for inhaled corticosteroids?

Chronic airway inflammation and inflammatory mediator production contribute to airway hyperresponsiveness, recurrent symptoms, and asthma exacerbations.

What is the drug target, target family and location for inhaled corticosteroids?

glucocorticoid receptors (GR), steroid hormone nuclear receptor, airway epithelial cells and inflammatory or immune cells in airways

What is the target logic and baseline function of the drug target for inhaled corticosteroids?

Endogenous cortisol binds GR, and the activated receptor modulates gene expression involved in inflammatory/immune responses and broader metabolic and homeostatic physiology. GR signaling is pleiotropic.

What is the pharmacologic activity and mechanism of action for inhaled corticosteroids?

agonist, activates GR, inducing broad changes in gene transcription that increase anti-inflammatory regulatory activity and decrease pro-inflammatory signaling.

What are the cellular and physiological effects of using inhaled corticosteroids?

Broad changes in gene expression reduce pro-inflammatory cytokine and mediator production and immune-cell activation. Reduced airway inflammation and hyperresponsiveness; improved airway function.

What are the therapeutic effects of inhaled corticosteroids?

Improved long-term asthma control; reduced symptoms and exacerbations.

What are the adverse effects of inhaled corticosteroids?

Oropharyngeal candidiasis from local immunosuppression; systemic corticosteroid effects with excessive or prolonged systemic exposure.

What is the disease relevant mechanism for histamine H1 receptor antagonists, first generation?

Excess local HA release during allergic reactions activates H1Rs, producing vascular leak and edema, sensory-nerve activation, and symptoms of allergic rhinitis and cutaneous allergy.

What is the drug target, target family and location for histamine H1 receptor antagonists, first generation?

histamine H1 receptor, GPCR, vascular endothelial cells or smooth muscle cells or sensory neurons

What is the target logic and baseline function of the drug target for histamine H1 receptor antagonists, first generation?

During normal local immune responses, HA released from mast cells and basophils activates H1Rs. H1R signaling through Gq-PLC-IP3-Ca²⁺ increases vascular permeability and vasodilation, promotes smooth muscle contraction, and stimulates sensory neurons.

What is the pharmacologic activity and mechanism of action for histamine H1 receptor antagonists, first generation?

reversible orthosteric antagonists, blocks HA binding to H1Rs reducing receptor activation

What are the cellular and physiological effects of using histamine H1 receptor antagonists, first generation?

Reduced Gq-PLC-IP3-Ca²⁺ signaling in H1R-expressing cells; reduced endothelial permeability/vasodilation, smooth muscle contraction, and sensory-nerve activation. Reduced local vascular leak and tissue edema; reduced histamine-mediated smooth-muscle and sensory responses.

What are the therapeutic effects of histamine H1 receptor antagonists, first generation?

Relief of allergic rhinitis and cutaneous allergy symptoms.

What are the adverse effects of histamine H1 receptor antagonists, first generation?

Sedation from central H1R blockade; dry mouth and urinary retention from off-target muscarinic receptor antagonism.

What is the disease relevant mechanism for histamine H1 receptor antagonists, second generation?

Excess local HA release during allergic reactions activates H1Rs, producing vascular leak and edema, sensory-nerve activation, and symptoms of allergic rhinitis and cutaneous allergy.

What is the drug target, target family and location for histamine H1 receptor antagonists, second generation?

histamine H1 receptor, GPCR, vascular endothelial cells or smooth muscle cells or sensory neurons

What is the target logic and baseline function of the drug target for histamine H1 receptor antagonists, second generation?

During normal local immune responses, HA released from mast cells and basophils activates H1Rs. H1R signaling through Gq-PLC-IP3-Ca²⁺ increases vascular permeability and vasodilation, promotes smooth muscle contraction, and stimulates sensory neurons.

What is the pharmacologic activity and mechanism of action for histamine H1 receptor antagonists, second generation?

reversible orthosteric antagonists, blocks HA binding to H1Rs reducing receptor activation

What are the cellular and physiological effects of using histamine H1 receptor antagonists, second generation?

Reduced Gq-PLC-IP3-Ca²⁺ signaling in H1R-expressing cells; reduced endothelial permeability/vasodilation, smooth muscle contraction, and sensory-nerve activation. Reduced local vascular leak and tissue edema; reduced histamine-mediated smooth-muscle and sensory responses.

What are the therapeutic effects of histamine H1 receptor antagonists, second generation?

Relief of allergic rhinitis and cutaneous allergy symptoms.

What are the adverse effects of histamine H1 receptor antagonists, second generation?

Somnolence can occur, but limited CNS exposure produces substantially less sedation than first-generation H1 antihistamines.

What is the disease relevant mechanism for leukotriene receptor antagonists?

Cysteinyl leukotrienes released during allergic inflammation activate CysLT1Rs, contributing to bronchoconstriction, airway edema and mucus, and inflammatory responses in asthma and allergic rhinitis.

What is the drug target, target family and location for leukotriene receptor antagonists?

cysteinyl leukotriene type 1 receptor (CysLT1R), GPCR, bronchiolar SMC, secretory SMC, vascular endothelial cells, eosinophils, and other inflammatory cells in the airway and nasal mucosa.

What is the target logic and baseline function of the drug target for leukotriene receptor antagonists?

During inflammatory and immune responses, cysteinyl leukotrienes activate CysLT1Rs. Receptor signaling promotes airway smooth muscle contraction, mucus production, vascular permeability, and inflammatory-cell recruitment or activation.

What is the pharmacologic activity and mechanism of action for leukotriene receptor antagonists?

reversible orthosteric antagonists, blocks cysteinyl leukotriene binding to CysLT1Rs, reducing receptor activation.

What are the cellular and physiological effects of using leukotriene receptor antagonists?

Reduced CysLT1R-dependent signaling in airway smooth muscle and inflammatory cells; reduced smooth muscle contraction and inflammatory activation. Reduced bronchoconstriction, airway edema and mucus, and allergic inflammation.

What are the therapeutic effects of leukotriene receptor antagonists?

Improved asthma maintenance and allergic rhinitis symptoms.

What are the adverse effects of leukotriene receptor antagonists?

neuropsychiatric effects but no direct mechanism

What is the disease relevant mechanism for beta lactams (penicillins, cephalosphorins, carbapenems)?

Growth of susceptible bacteria in respiratory tissues depends on peptidoglycan cross-linking to maintain cell-wall integrity; bacterial proliferation drives infection and host inflammation.

What is the drug target, target family and location for beta lactams (penicillins, cephalosphorins, carbapenems)?

transpeptidase (or PBP), serine transpeptidase enzyme, bacterial cell envelope or membrane-associated PBP act at the peptidoglycan wall

What is the target logic and baseline function of the drug target for beta lactams (penicillins, cephalosphorins, carbapenems)?

In growing bacteria, PBPs catalyze transpeptidation that cross-links peptidoglycan strands, maintaining cell-wall strength and resistance to osmotic stress.

What is the pharmacologic activity and mechanism of action for beta lactams (penicillins, cephalosphorins, carbapenems)?

irreversible competitive inhibitor, covalently acetylates the active-site serine of PBP

What are the cellular and physiological effects of using beta lactams (penicillins, cephalosphorins, carbapenems)?

Defective peptidoglycan cross-linking produces progressive cell-wall weakness and osmotic instability during bacterial growth. Reduced bacterial viability and pathogen burden, with reduced ongoing microbial stimulation of host inflammatory responses.

What are the therapeutic effects of beta lactams (penicillins, cephalosphorins, carbapenems)?

Bactericidal activity against susceptible pathogens; improvement or resolution of bacterial respiratory infection.

What are the adverse effects of beta lactams (penicillins, cephalosphorins, carbapenems)?

Bacterial resistance can arise through beta-lactamase-mediated drug hydrolysis, carbapenemases for gram-negative bacteria or altered PBPs; antibacterial activity against commensal bacteria can disrupt the microbiome and cause diarrhea.

What is the disease relevant mechanism for glycopeptides?

Growth of susceptible Gram-positive bacteria depends on peptidoglycan assembly to maintain cell-wall integrity; bacterial proliferation drives infection and host inflammation.

What is the drug target, target family and location for glycopeptides?

D-Ala-D-Ala terminus of cell wall peptidoglycan precursor, n/a, bacterial cell envelope