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411 Section 2: Drug Receptors FLASHCARDS

Drug Receptors and Ligand Interactions: Comprehensive Notes

  • Overview: Drugs interact with biological targets (receptors) to alter cellular metabolism and physiology through defined activation pathways.

Receptor Activation: Three General Routes (Mechanisms of Action)

  • Route 1: Direct Modulation of Ion Channels (Ion Channel Receptors) “Channel-linked receptors-A”

    • Receptor type spans the membrane and forms an ion channel pore upon ligand binding.

    • Example: Acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction.

    • Mechanism: Ligand binding opens a pore, increasing membrane permeability to a specific ion (e.g., Na^+), causing depolarization and muscle excitation.

    • Other channel example: GABA receptors (GABAA and GABAC) are ligand-gated chloride channels; activation increases Cl^- permeability leading to hyperpolarization; GABA_B involves potassium efflux.

  • Route 2: Surface Receptors Linked Directly to Enzymes “Enzyme-Linked Receptors-B” (Catalytic Receptors)

    • Receptors span the membrane and have an extracellular binding site and an intracellular catalytic domain.

    • Key example: Receptor tyrosine kinases (RTKs).

    • Upon ligand binding, the receptor activates enzymatic activity within the cell, propagating a signaling cascade. - Figure C-

  • Route 3: Surface Receptors Linked to Regulatory G Proteins (G Protein–Coupled Receptors, GPCRs) → Second Messengers- “G-protein-receptors-C”

    • Receptors engage intracellular regulatory G proteins upon ligand binding.

    • G proteins are activated by the exchange of GDP for GTP and then regulate downstream effectors to generate second messengers.

    • First Messenger: The ligand (hormone, neurotransmitter) that binds the receptor.

    • Second Messengers: Small molecules (e.g., cyclic AMP, Ca^{2+}, cyclic GMP) that transduce the signal inside the cell.

    • The second messenger system connects membrane events to internal metabolic machinery.

  • Note on Amplification: The cascade amplifies the signal—one ligand-receptor interaction can activate multiple downstream enzymes and second messengers.

Key Concepts in Drug-Receptor Pharmacology

  • Ligand: A substance that forms a complex with a biomolecule to serve a biological purpose; ligands alter receptor conformation and function.

  • Receptor: A cell component where a drug/hormone binds to initiate biochemical events; binding causes a conformational change and altered cellular function.

  • Lock-and-key model: Initial simplistic view of receptor recognition; actual interactions involve induced fit and conformational changes.

  • Surface Receptors: Can influence cells via ion channels, enzymes, or regulatory proteins.

- Second Messenger Signaling

  • Second Messenger Signaling: Involves the activation of intracellular signaling cascades triggered by surface receptor interaction, leading to a variety of cellular responses, such as changes in gene expression, enzyme activity, or ion channel permeability.

  • Two Important Second Messengers:

    • Cyclic AMP (cAMP): This molecule plays a key role in transmitting signals from neurotransmitters and hormones, often activating protein kinases that subsequently phosphorylate target proteins.

    • Calcium Ions (Ca²⁺): Calcium acts as a versatile second messenger that influences various cellular processes, including muscle contraction, secretion, and gene regulation.

    • Protein Kinase: Enzymes that modify other proteins by chemically adding phosphate groups, thereby altering the activity and function of the target proteins. Protein kinase activation can be initiated by both cAMP and Ca²⁺, leading to a cascade of intracellular events that ultimately result in a physiological response.

    • G Protein Synthesis is altered in certain pathologic conditions, which can disrupt normal signaling pathways and contribute to various diseases. Examples like alcoholism, DM, heart failure and certain tumors.

Affinity, Selectivity, Efficacy, Agonists, and Antagonists

  • Affinity: The strength of attraction between a drug and its receptor.

  • Selectivity: Preference of a drug for a particular receptor or tissue. Characteristic of Agonist

  • Efficacy (Intrinsic Activity): The ability of a bound drug to activate the receptor and produce a cellular response.Characteristic of agonists

  • Agonist: A drug that binds to a receptor and initiates a metabolic change in the cell.

  • Partial Agonist: Produces an incomplete or submaximal response even at full receptor occupancy.

  • Antagonist: Binds to the receptor with no intrinsic efficacy, blocking agonist action.

  • Competitive Antagonist: Competes with an agonist for the same binding site; effect can be overcome by higher agonist concentration.

  • Non-competitive Antagonist: Binds to a different site or inactivates the receptor in a way not overcome by more agonist. Covalent bond.

  • Allosteric Regulation: A Regulatory molecule binds at a site other than the active site to modulate receptor activity. Shut down mechanism- “Blocker”

Allosteric Sites

  • Allosteric site: Regulatory binding site distinct from the active site; binding can enhance or inhibit receptor function.

Receptor Regulation and Adaptation

  • Desensitization: Brief, transient decrease in responsiveness due to overstimulation (tolerance).

  • Down-Regulation: Prolonged exposure leads to receptor removal or reduced synthesis/function; results in reduced receptor activity.

  • Up-Regulation: Increased receptor synthesis with heightened sensitivity due to reduced exposure to ligand.

  • Negative feedback: Both down-regulation and desensitization serve to prevent overstimulation by an agonist.

Specific Autonomic Receptors

Cholinergic Receptors (ACh Receptors)

Autonomic Nervous System

Parasympathetic Nervous System: Rest-Vagus Nerve- ex: decrease heart rate, increase digestion, bronchoconstriction: stimulates lung expansion

Sympathetic: Fight or Flight

Cervical Spine-largest nerve

thoracic-lots of ganglia- due to organ function

ganglia: group of neurons/cell bodies outside CNS-nicotinic receptors:preganglia, postganglionic: distal

- nuclei- inside CNS

- ACh-both in para and sympathetic nervous system, nicotinic receptor

  • Located at acetylcholine synapses; subdivided into nicotinic and muscarinic receptors (autonomic focus).

  • Nicotinic receptors: PARASYMPATHETIC

    • Ligand-gated; high affinity for nicotine. Open Ion channel

    • Will move to the muscarinic receptor

    • Located at the synapse between autonomic preganglionic and postganglionic neurons; mediates transmission in both parasympathetic and sympathetic pathways; also at the neuromuscular junction.

    • Ach(Acetylcholine): Main neurotransmitter that activates these receptors, leading to depolarization of the postsynaptic membrane and facilitating neurotransmission.

    • The vagus nerve plays a crucial role in parasympathetic control by activating acetylcholine (ACh) receptors, which mediate various bodily functions such as heart rate reduction and gastrointestinal activity.

  • Muscarinic receptors:

    • G-protein-coupled receptors with affinity for muscarine-toxic gas?WW2?

    • Located between postganglionic cholinergic neurons and terminal effector cells; all parasympathetic terminal synapses; sweat glands receive sympathetic cholinergic input.

    • Five subtypes; effects include contraction of visceral/bronchiolar smooth muscle, decreased heart rate, and increased secretion from exocrine glands (salivary, intestinal, lacrimal).

Adrenergic (Autonomic) Receptors (APA: Alpha and Beta Receptors)-adrenaline-based hormones and drugs

  • Alpha (α) and Beta (β) receptors are located on effector cells between sympathetic postganglionic neurons and tissues.SYMPATHETIC-postganglionic-epi/norepi-on effector cell-catacolamine

  • Alpha-1 (α1):

    • Primary location: smooth muscle of vasculature (peripheral vasculature, intestinal wall, iris, ureters, urinary sphincter).

    • Stimulation: Vascular/urinary smooth muscle contraction; intestinal relaxation. Vasoconstriction occurs in response to α1 receptor stimulation, leading to increased blood pressure and decreased blood flow to certain areas.

    • vasodilator- increases blood flow, shuts off alpha receptor

  • Alpha-2 (α2):

    • Primary location: Spinal interneurons and CNS adrenergic synapses.

    • Stimulation: Reduces neuronal excitability; may inhibit sympathetic discharge from the brainstem.

    • protein receptors, struggle to hit BBB, causes relaxation

  • Beta-1 (β1):

    • Predominant in the heart and kidney. But all through the body…

    • Stimulation: Increases heart rate and contractility, as well as renin secretion.

    • Kidney: synthesizes the hormone renin, an enzyme that plays a crucial role in regulating blood pressure and fluid balance in the body. Angiotensinogen- adipose issue-liver-protein-blood stream: A precursor to angiotensin, it is converted in the liver to angiotensin I, which is then further processed to angiotensin II, a potent vasoconstrictor that helps regulate blood pressure-increase plasma volume-increase heart rate. Aldosterone-aquaporin system- systemic circulation- sodium mechanism- osmosis draw- mineralocorticoid- antidiuretic-urine

    • ACE inhibitor: A class of medication that blocks the conversion of angiotensin I to angiotensin II, leading to decreased blood pressure, reduced cardiac workload, and improved heart function.

    • ACE 2: Ang-17-antifibrotic-antiinflamatory- dilation of blood vessels-tissue healing and remodelling

  • Beta-2 (β2):

    • Located in smooth muscle of bronchioles, certain vasculatures, gallbladder, uterus; also in cardiac muscle. adrogernic-postganglionic

    • Stimulation: Bronchodilation; metabolic effects on skeletal muscle and liver.

  • Beta-3 (β3):

    • Located mainly in adipose tissue; stimulation increases lipolysis; also present in cardiac and some smooth muscle.

  • glucocortamine-obesity-metabolism-metabolic conditions influence the regulation of appetite and energy expenditure, thereby playing a significant role in obesity-related metabolic conditions.

Adenosine Receptors hold plasma volume

  • G-protein coupled receptors (four known types in humans) with mainly inhibitory (Gi) signaling.

  • Effects of stimulation:

    • Sedative effect on cardiac and neural tissue; reduces presynaptic neurotransmitter release; reduces SA node activity; coronary artery dilation. Hyperpolarization-calcium channels, snare proteins, and various intracellular signaling pathways are also influenced by adenosine receptor activity, contributing to the overall modulation of excitability and neurotransmitter dynamics in the central nervous system.

    • Kidney effects: modulates vascular and tubular function; reduces glomerular filtration rate and NaCl elimination; leads to arteriolar effects. Reduces nephrons at the kidneys-reduce filtration-diaretic=caffine-more blood to also filter

    • CNS: Inhibition of synaptic transmission and reduction of excitability.

  • A1 receptor: Activates K^+ channels and inhibits Ca^{2+} channels, contributing to the above effects.

  • High on Adenosine=low energy, groggy, SLEEP

Opioid Analgesics: Morphine and Receptors- Opium

  • Morphine: Prototypical opioid analgesic=pain reducing; other opioids include fentanyl, hydromorphone, meperidine, methadone, oxycodone, hydrocodone, codeine.

  • Opioid terminology:

    • Opiates: Historically derived from opium.

    • Opioids: All narcotic, analgesic-like agents; broader than traditional opiates.

    • Narcotic: Sleep-inducing/sedative side effect, not the primary therapeutic action.

  • Opioid receptors: Mu, Kappa, Delta, and ORL-1 (opioid receptor-like 1). Produce this on our own- “Endorphines”- “tetrahydrocannabinol”

  • Mu receptors: Central to analgesia; high-affinity ligands produce analgesia but also respiratory depression, constipation, and risk of addiction.

  • Kappa receptors: Analgesia with less respiratory depression and lower addiction potential; may cause dysphoria, depression, and anxiety. These are heightened when stimulated

  • Delta receptors: Contribute to analgesia and other CNS effects (not detailed in slides).

  • ORL-1 (also called nociceptin receptor): Modulates pain and other effects (less emphasized in slides).

Pharmacotherapeutics of Opioids

Pharmacokinetics (PK)

  • Routes of administration: Oral preferred when possible; suppositories if nauseated/vomiting; some opioids require parenteral administration due to high first-pass metabolism.

  • Distribution: Reached throughout tissues, including CNS.

  • Metabolism: Primarily in liver and tissues (kidneys, lungs, CNS).

  • Excretion: Kidneys excrete metabolites.

Pharmacodynamics (PD) – Mechanism of Analgesia

Afferent-PNS CNS

Efferent-CNS Effector Organ-inhibit reaction to pain- less inflammatory

  • Primary action: Inhibit afferent pain transmission in ascending pathways at nociceptive synapses.

  • Presynaptic effects: Opioid receptors on presynaptic nociceptive afferents reduce the release of substance P by decreasing Ca^{2+} influx.

  • Postsynaptic effects: Activation of G-proteins leads to opening of K^+ channels (hyperpolarization) and decreased neuronal excitability; reduced pain signaling.

  • Descending modulation: Opioids activate descending pain control pathways from higher brain centers to modulate interneurons.

  • Peripheral effects: Anti-inflammatory actions contributing to pain relief.

  • Second messenger involvement: G-protein coupling inhibits Ca^{2+} channels and modulates downstream signaling; encompasses the classic cAMP pathway and other second messengers.

Opioid Addendum – Endosomal Signaling

  • Mu receptor activation can also stimulate endosome signaling, which can alter adenylyl cyclase activity within endosomal compartments, adding another layer of receptor regulation.

  • Endosomes: Intracellular sorting organelles involved in trafficking ligands; implications for receptor signaling and cellular response.

Non-Receptor Drug Mechanisms (Contrast to Receptor-Mediated Actions)

  • Chemotherapeutic Antimetabolites:

    • Involved with protein synthesis and specific genes.

    • Act as improper ingredients (nucleotides) in biosynthesis; hinder DNA base synthesis.

    • Affects synthesis of harmful/unwanted materials and hinders biosynthesis of required components.

  • Antacids: Hydroxide bases (OH^-) that directly neutralize stomach acid via acid-base reactions (not receptor-mediated).

Additional Context: Key Terms and Concepts Summary

  • Ligand: Substrate, inhibitor, activator, signaling lipids, neurotransmitters that bind to receptors.

  • Receptor: A cell component where ligands bind to initiate biochemical events and alter metabolism.

  • Second Messengers: Small molecules (e.g., cAMP, Ca^{2+}, cGMP) that propagate signals inside the cell and activate kinases.

  • Protein Kinases: Enzymes that transfer phosphate groups from ATP to target proteins, propagating signaling cascades.

    • General reaction: ext{Protein} + ext{ATP}
      ightarrow ext{Protein-}P + ext{ADP}

  • G Proteins: Molecular switches activated by ligand-bound GPCRs; GDP replaces by GTP to turn the protein "on"; regulate downstream effectors.

  • General signaling cascade: Ligand → Receptor → G protein/Enzyme → Second messengers → Kinases → Cellular response.

Public Health and Statistics (Referenced in Slides)

  • 2.1 million Americans addicted to prescription pain medication.

  • Drug advertising legal since 1990; contributed to increased prescriptions.

  • 2011: ~4 billion prescriptions in the US.

  • Over 1.4 billion opioid overdoses treated in ER annually (note: phrasing in slides suggests ER visits per year).

  • 22,000 people die each year due to prescription drug overdoses.

  • Mortality estimates: up to 47,000 deaths in 2015; > 77,000 deaths in 2017.

  • Source references included in slides: Today Health (2013) and related materials.

  • Connections to foundational principles:

    • Structure–function relationships: ligand binding induces conformational changes in receptors, altering function.

    • Signal transduction: amplification and divergence through cascades allow small signals to affect large cellular outputs.

    • Regulation and homeostasis: desensitization, up-/down-regulation prevent overstimulation and maintain balance.

    • Pharmacokinetics/pharmacodynamics: routes of administration, metabolism, and receptor interactions determine drug effects and safety.

  • Ethical and practical implications:

    • Prescription drug abuse and addiction risk highlighted by statistics.

    • Pharmacovigilance and responsible prescribing are critical in mitigating overdose deaths.

    • Understanding receptor pharmacology informs safer analgesic use and development of targeted therapies with fewer side effects.