Membrane Potentials, Pharmacology, and Neoplasia Notes

Membrane Potentials and Action Potentials

• Overview aims (from transcript):
  • Transport of substances through cell membrane (CM)
  • Nerve resting membrane potential (MP)
  • Nerve action potential (AP)
  • Propagation of AP along nerve
  • Re-establishing Na^+ and K^+ gradients after AP: role of energy metabolism
  • APs in special excitable tissues (plateau and repetitive discharges)
  • Signal transmission in nerve trunks
  • Practical examples illustrating concepts

Cell Membrane Structure and Transport Mechanisms

• CM composition:

  • Lipid bilayer of phospholipids forming a barrier
  • Numerous proteins with various functions; some proteins protrude through/beside the bilayer
  • Carbohydrate moieties attached to proteins (glycoproteins)

• Extracellular (EC) vs intracellular (IC) fluids:

  • Concentration differences across CM are key for cell life

• Transport through CM:

  • Protein components enable transport: channel/pore proteins (water-filled channels) and carrier proteins (bind specific substrates)
  • Lipid-soluble substances can cross CM without proteins or ion channels

• Transport pathways (through CM):

  • Simple diffusion
  • Facilitated diffusion (carrier-mediated)
  • Active transport (carrier-mediated and energy-dependent)

• Key notes:

  • Lipid-soluble substances: more permeable through lipid bilayer
  • Small molecules/ions: more permeable via water-filled channels/pores

• Simple diffusion and channels:

  • Channels are protein conformations that open/close gates (gating)
  • Types of gating: voltage-gating and ligand (chemical) gating
  • Ions move down their concentration gradients when gates open

• Figures and recap references:

  • Charge and diffusion gradients drive MP and ion movement
  • Water-filled channels vs lipid bilayer permeability depend on size, charge, and lipophilicity

Transmission Across CM: Detailed Transport Mechanisms

• Substances enter/leave cells via 3 main processes:

  • Simple diffusion
  • Facilitated diffusion (carrier-mediated); saturable (Vmax)
  • Active transport (carrier-mediated and energy-dependent)

• Facilitated diffusion (carrier-mediated):

  • Molecule binds to carrier protein
  • Carrier undergoes conformational change to move molecule inside
  • Diffusion rate approaches maximum (Vmax) as binding sites saturate
  • Examples: transport of glucose and most amino acids

• Simple diffusion specifics:

  • No carrier proteins required
  • Lipid-soluble substances cross more readily
  • Small molecules/ions can use water-filled channels

• Ion channels and gating (focus on Na^+ and K^+ channels):

  • Ion channels form gated pathways in CM
  • Activation/inactivation gates regulate flow
  • Opening allows ions to diffuse down electrochemical gradients

• Key questions to understand channels:

  • What is a sodium channel? a potassium channel?
  • Are channels always open? How is gating controlled?
  • Differences between voltage gating and ligand gating

• Visual recap (from slides):

  • Na^+/K^+ channels gate with changes in membrane potential and binding ligands
  • Controlled gating underpins AP initiation and propagation

Resting Membrane Potential (RMP) and Diffusion Potentials

• Electrical potentials exist across all cell membranes; excitable tissues (nerve, muscle) can propagate electrochemical impulses

• Resting MP arises primarily from diffusion potentials of key ions, especially K^+ and Na^+

• Metered potentials:

  • When membrane is permeable only to K^+: K^+ diffuses outward, internal MP becomes negative
  • When membrane is permeable only to Na^+: Na^+ diffuses inward, MP becomes positive

• Characteristic diffusion potentials (Nernst potentials):

  • K^+ diffusion potential ≈ −94 mV
  • Na^+ diffusion potential ≈ +61 mV

• Nernst equation for a single ion:

  • E{ion} = ext{±} 61 \, ext{log}{10}rac{Ci}{Co} \, ext{mV}
  • For K^+: E_K \approx -94 \, \text{mV}
  • For Na^+: E_{Na} \approx +61 \, \text{mV}

• Direct measurement tools: microelectrodes can measure membrane potential

• Goldman-Hodgkin-Katz (GHK) perspective (for multiple ions):

  • Em = \frac{RT}{F} \ln\left( \frac{PK[K^+]o + P{Na}[Na^+]o + P{Cl}[Cl^-]i}{PK[K^+]i + P{Na}[Na^+]i + P{Cl}[Cl^-]_o} \right)
  • Explains resting MP when multiple ions contribute with different permeabilities

• The Na^+/K^+ ATPase (pump) contributes a small but important component to MP

  • Na^+-K^+ pump activity contributes approximately −4 mV to resting MP
  • Pump helps re-establish ion gradients after APs

Establishment of Resting Membrane Potentials in Nerve Fibers

• Resting MP can be thought of in terms of ion fluxes and pump activity under 3 conditions:
  • A) Resting MP caused entirely by K^+ diffusion: about −94 mV
  • B) Resting MP caused by diffusion of both Na^+ and K^+: about −86 mV
  • C) Combined diffusion of Na^+ and K^+ plus Na^+-K^+ pump activity: about −90 mV
• The dominant determinant is K^+ leak diffusion (roughly 100× more permeable than Na^+ leak)
• Goldman equation is used to describe MP when multiple ions permeate the membrane

Nerve Action Potential (AP)

• AP definition: rapid change in MP from resting (negative) to positive, then back to negative

• AP propagation along the nerve: AP moves along the fiber to the end

• Three key phases: Resting, Depolarization, Repolarization

• Key channels involved:

  • Voltage-gated Na^+ channels: responsible for depolarization and, to a lesser extent, repolarization
  • Voltage-gated K^+ channels: increase rate of repolarization

• Sequence of events in AP (brief):

  • Resting MP (negative)
  • Threshold reached → rapid opening of Na^+ channels → depolarization
  • Inactivation of Na^+ channels and delayed opening of K^+ channels → repolarization
  • Hyperpolarization briefly occurs as K^+ channels remain open

• Recording APs: typical AP shows transient rapid depolarization followed by repolarization

• Core review questions (from slides):

  • What initiates the AP?
  • Diffusion of which ion determines magnitude of the resting MP?
  • Diffusion of which ion determines rate/extent of AP?
  • What is an electrogenic pump?

• Na^+ conductance increases dramatically early in AP; K^+ conductance increases later

• Na^+ conductance rise is several thousand-fold; K^+ rise is ~30-fold in the latter stage

• After-hyperpolarization (AHP): due to prolonged K^+ channel opening

• Recharging the membrane (repolarization) involves K^+ efflux from IC to EC

Action Potential in Special Tissues and Plateaus

• Cardiac cells (Purkinje fibers) exhibit an AP plateau: a sustained depolarized state
  • Plateaus primarily due to slow opening of voltage-gated Ca^{2+} channels and slower activation of K^+ channels
  • Contrast with skeletal muscle APs, which lack a plateau
• Rhythmically excitable tissues (e.g., intestinal smooth muscle) show repetitive discharges with Ca^2+ involvement
• Nerve/APs and skeletal muscle APs share many similarities, but cardiac APs include a plateau phase due to Ca^{2+} influx

Propagation of Action Potentials and Nerve Trunks

• Propagation mechanism (normal nerve fiber):
  • AP at one site depolarizes adjacent membrane, triggering a new AP, propagating in both directions from the initiation point
• Myelinated vs unmyelinated fibers:
  • Myelinated fibers conduct faster due to saltatory conduction (APs jump from node to node)
  • Velocity depends on fiber diameter and degree of myelination
• Nodes of Ranvier: gaps where ion flow occurs; myelin sheath insulates and concentrates ion flow at nodes
• Schwann cells form the myelin sheath in the peripheral nervous system; they also aid in regeneration
• Saltatory conduction significantly increases conduction velocity compared to continuous conduction in unmyelinated fibers

Saltatory Conduction and Myelination (Functional Significance)

• Functional significance of Schwann cell myelin:
  • Insulation of nerve fibers, rapid conduction, and guidance for nerve regeneration after injury
• Saltatory conduction: current flow from node to node rather than along the entire membrane
• Conduction velocity correlates with axon diameter and myelination

Stimulus Effects, Thresholds, and Neuromuscular Junction (NMJ)

• Stimulus and AP: there is a threshold below which subthreshold potentials occur; below threshold no AP (none-or-all response when threshold is reached)
• Neuromuscular junction (NMJ) and excitation-contraction coupling
• Adrenergic terminal and neurotransmitter release:
  • Norepinephrine (NE) stored in vesicles is released when AP reaches the terminal
  • NE acts on α- and β-adrenergic receptors at the effector cell
  • α-receptors cause vasoconstriction and increased arterial pressure; β-receptors increase heart rate and contraction force
• Local anesthetics (LAs) like lidocaine block initiation and propagation of AP by inhibiting Na^+ conductance at nerves
• Mechanism of LA action: likely blocks Na^+ channels by interacting with intracellular domains, reducing pain transmission by sensory nerve blockade

Review: Summary of Membrane and Nerve Excitability Concepts

• MP and AP are governed by ion concentration gradients, ion channel permeabilities, and energy-dependent pumps
• Resting MP arises mainly from K^+ leak and Na^+/K^+ pump contributions
• AP entails rapid Na^+ influx (depolarization) followed by K^+ efflux (repolarization)
• Propagation relies on local circuit currents and, in myelinated fibers, saltatory conduction
• NMJ and autonomic neurotransmission illustrate practical applications (drug effects, anesthesia, and autonomic regulation)

Pharmacology: Foundations and Drug-Receptor Interactions

• Pharmacology defined:

  • Pharmacology: science of interactions between drugs and biological systems
  • A drug: any chemical that produces an effect on cells, tissues, or organs
  • A medicine: a drug used for prevention, diagnosis, or treatment
  • Pharmacy: practice of preparing and dispensing medicines
  • Toxicology: study of poisons, their actions, detection, and treatment

• Major subdivisions:

  • Pharmacodynamics: mechanisms of drug action and structure-activity relationships (SAR)
  • Pharmacokinetics: absorption, distribution, metabolism, and excretion (ADME)
  • Pharmacotherapeutics: proper drug use, indications, contraindications, dosing, duration, side effects, interactions, toxicity

• Drug fate (kinetics) outline (example flow):

  • Administration → gut absorption → liver (first-pass) → systemic circulation → site of action (receptors) → metabolism → excretion
  • Tissue reservoirs and free drug balance with plasma proteins

• Pharmacodynamics (mechanisms of drug action):

  • Most drugs act with some receptor specificity at appropriate doses
  • Receptors are macromolecules that mediate drug effects
  • Drugs can modify existing functions rather than create entirely new functions
  • Some drugs act without receptors (e.g., anticholinesterase inhibitors)

• Acetylcholine (ACh) as a neurotransmitter example:

  • Increases secretion, lowers blood pressure, stimulates muscle contraction
  • Receptors: Muscarinic and Nicotinic; cholinesterase regulates acetylcholine
  • Anticholinesterase (e.g., pyridostigmine) treats myasthenia gravis; irreversible inhibitors (like organophosphates) used in nerve agents
  • Muscarinic agonists (e.g., pilocarpine); neuromuscular blockers (e.g., succinylcholine)

• Receptor characterization and pharmacology concepts:

  • Receptors are classic targets for drug action; binding is usually reversible; receptor resembles a switch with ON/OFF states
  • Receptors are grouped into major families:
  • Ion channel-linked receptors (ligand-gated; e.g., nicotinic, GABA receptors)
  • G-protein-coupled receptors (GPCRs; e.g., adrenergic receptors)
  • Enzyme-linked receptors (e.g., insulin receptor)
  • Intracellular (nuclear) receptors (for lipophilic drugs; e.g., steroid receptors)
  • Lock-and-key concept: drugs fit receptors like keys fit locks

• Major receptor classes (high-level):

  • Ion channel-linked receptors: ligand-gated ion channels
  • G-protein-coupled receptors: signal amplification via G-proteins, second messengers, and gene regulation
  • Enzyme-linked receptors: receptor tyrosine kinases and downstream signaling
  • Intracellular receptors: nuclear receptors affecting transcription

• Binding forces in drug-receptor interactions (major bonds):

  • Covalent (irreversible, uncommon)
  • Ionic
  • Hydrogen bonds
  • Van der Waals forces
  • Hydrophobic interactions
  • Cation-π interactions
  • Cooperative binding effects

• Epinephrine and beta-adrenergic receptor example:

  • Involves Van der Waals, ionic, and hydrogen bonds in receptor binding

• Structure-Activity Relationships (SAR) and pharmacophore concept:

  • Pharmacophore: molecular features necessary for receptor recognition
  • Involve ionic charges, hydrogen bonding potential, steric factors, and 3-D configuration
  • Pharmacophore-guided modifications can improve potency or create new effects

• Drug-receptor pharmacophore example: antimuscarinics

  • Common pharmacophore features shown (four R groups and core structure variations)

• Consequences of drug binding: allosteric regulation and indirect effects

  • Allosterism: ligand binds at an allosteric site, changing receptor conformation and activity

Dose-Response Relationships and Pharmacodynamics Concepts

• Dose-Response Relationships (DRR):

  • Magnitude of response generally increases with drug concentration (occupancy theory)
  • DRR is not linear across all concentrations
  • Occupation theory: D + R ⇄ DR → Effect

• Dose-response curve shapes:

  • Hyperbolic response curve
  • Log-dose response curve: sigmoid, with thresholds and ceilings; linear-ish between 25–75% response
  • ED50: dose that gives 50% of maximal response

• Affinity vs intrinsic activity (efficacy):

  • Affinity: ability of agonist to bind receptor
  • Intrinsic activity (efficacy): ability of bound agonist to activate receptor function

• Agonists and antagonists:

  • Agonist: binds with affinity and intrinsic activity; can be full or partial
  • Antagonist: binds with affinity but has little or no intrinsic activity
  • Partial agonist: binds with high affinity but elicits submaximal response regardless of occupancy

• Types of antagonists:

  • Competitive (surmountable): shifts curve to the right without changing max response
  • Noncompetitive: reduces max response

• Receptor occupancy vs response limitations:

  • Existence of spare receptors can decouple occupancy from maximal response
  • Receptor subtypes, inverse agonists, desensitization (receptor down-regulation) influence responses

• Allosteric and two-state models:

  • Some effects reflect allosteric modulation or two-state receptor dynamics

• Receptor-independent actions (examples):

  • Chemically reactive agents (e.g., Mg(OH)_2 antacids)
  • Osmotic/paracrine effects (e.g., MgSO4 as a cathartic)
  • Thymine analogue incorporation into genetic material (5-bromouracil) in cancer therapy

• Drug response variations:

  • Drug resistance: loss of effectiveness with prolonged use (e.g., antibiotics)
  • Intolerance: increased response within therapeutic range (e.g., sedative effects)
  • Tolerance: gradual decrease in response requiring higher doses
  • Tachyphylaxis: rapid loss of response with repeated dosing
  • Idiosyncrasy: unusual adverse effect in a minority of patients (e.g., aspirin-induced asthma, G6PD deficiency–triggered hemolysis with fava beans or drugs)

• Practical implications:

  • Drug development targets signaling pathways and receptor interactions
  • Anticancer strategies include targeting oncogenes, tumor suppressors, and signaling cascades
  • Pharmacotherapy requires understanding potency, efficacy, and safety margins

Cancer, Neoplasia, and Pathology Foundations

• Neoplasia basics:

  • Neoplasm: new growth; swelling or tissue destruction due to unregulated, irreversible, monoclonal cellular proliferation
  • Distinct from hyperplasia and tissue repair; neoplasia persists after stimulus removal
  • Tumor and neoplasm are often used interchangeably in common language but have distinct nuances
  • Neoplasia can be benign, precancerous (premalignant), or malignant (cancer)

• Epidemiology and significance (US-focused data from slides):

  • Cancer is the second leading cause of death in adults and children
  • 2024 US estimates: >2,000,000 new cancer cases and >600,000 cancer deaths; health costs > $88 billion annually
  • Leading causes of death in the US (broad):
  • Cardiovascular diseases ~31%
  • Cancer ~23%
  • COVID-19 ~18%
  • Lung diseases ~9%
  • Cerebrovascular diseases ~7%
  • Accidents ~4%
  • Diabetes ~3%
  • Alzheimer’s ~2%

• Top cancer sites by incidence (examples from slides):

  • Prostate, Lung & bronchus, Colon & Rectum, Urinary bladder, Melanoma of the skin, Non-Hodgkin lymphoma, Kidney & renal pelvis, Oral cavity & pharynx, Leukemia, Pancreas
  • Note: data tables included per year; values illustrate relative burden and distribution by sex

• Benign vs malignant tumors (key distinctions):

  • Benign: slow growth, local, well-circumscribed, encapsulated, non-invasive, good prognosis
  • Malignant: invasive, destructs surrounding tissues, metastasizes, variable prognosis
  • Features to compare: margins, invasion, metastasis, differentiation, nuclear morphology

• Tumor nomenclature (examples):

  • Fibrous tissue: fibroma, fibrosarcoma
  • Fat: lipoma, liposarcoma
  • Cartilage: chondroma, chondrosarcoma
  • Bone: osteoma, osteosarcoma
  • Blood vessels: hemangioma, angiosarcoma, Kaposi sarcoma
  • Smooth muscle: leiomyoma, leiomyosarcoma
  • Striated muscle: rhabdomyoma, rhabdomyosarcoma
  • Epithelial: papilloma, squamous cell carcinoma; adenoma, adenocarcinoma
  • Melanocyte: nevus, melanoma
  • Lymphoid: lymphoid hyperplasia (polyclonal), lymphoma/leukemia

• Growth patterns and margins (benign vs malignant):

  • Benign: well-defined margins; often encapsulated
  • Malignant: poorly defined/infiltrative margins; potential for metastasis

• Precancerous lesions and progression:

  • Precancerous disease includes epithelial dysplasia and carcinoma in situ
  • Dysplasia: abnormal cellular organization of epithelium; irreversible genetic changes; may progress to invasive cancer if untreated
  • Barrett’s esophagus: intestinal metaplasia in esophagus due to GERD; goblet cells present; 30× increased risk of esophageal adenocarcinoma
  • Classic progression: normal epithelium → hyperplasia/metaplasia → dysplasia → carcinoma in situ → invasive carcinoma

• Barrett’s esophagus (a detailed example):

  • Normal esophagus lined by squamous epithelium; Barrett’s shows columnar epithelium with goblet cells replacing the squamous lining
  • Risk: Barrett’s esophagus markedly increases risk of esophageal adenocarcinoma
  • Visualization: esophagus with Barrett’s mucosa; transition from squamous to columnar epithelium

• Carcinogenesis and genetic basis:

  • Neoplasia is driven by genetic and chromosomal alterations (somatic and/or germline mutations)
  • Key gene categories: proto-oncogenes (g rowth-promoting), tumor suppressor genes (inhibit growth), regulators of apoptosis, DNA repair genes
  • Oncogene activation or tumor suppressor loss leads to uncontrolled growth and survival advantage
  • Monoclonality: neoplastic cells derived from a single progenitor cell; clonality can be assessed via markers (e.g., G6PD isoforms)

• Hallmarks of cancer (conceptual framework):

  • Sustained proliferative signaling
  • Evading growth suppressors
  • Resisting cell death
  • Enabling replicative immortality
  • Inducing angiogenesis
  • Activating invasion and metastasis

• Intracellular and extracellular signaling in cancer biology:

  • Growth factor receptors (e.g., EGFR, HER2) and downstream signaling drive proliferation
  • Genetic alterations in signal transduction pathways can lead to uncontrolled growth

• Viral and environmental etiologies:

  • Viruses: HPV (cervical, oropharyngeal cancers), EBV, other oncogenic viruses
  • Tobacco and alcohol: major chemical and lifestyle risk factors; synergistic effects on upper aerodigestive cancers
  • Radiation and other carcinogens (asbestos, chemicals) contribute to cancer risk
  • Obesity is associated with a sizable fraction of cancer deaths

• Cancer screening and prevention:

  • Pap smear, mammography, PSA testing with DRE, and colonoscopy are key screening tools
  • No reliable screening tool exists for some cancers (e.g., oral cancer) aside from clinical exams and knowledge-based assessments

• Tumor progression and metastasis:

  • Metastasis is defined as the spread of cancer from the primary site to distant sites via lymphatics, blood, or direct seeding (transcoelomic spread)
  • Metastasis is the defining feature of malignant neoplasms
  • Common metastasis pathways include lymphatic spread to lymph nodes, hematogenous spread to distant organs (e.g., liver, lungs, bone), and direct seeding in body cavities

• Case study highlights (selected):

  • Metastatic breast adenocarcinoma in a patient with neck/oral metastasis
  • Oral cavity metastases from distant primaries and immunohistochemical/biomarker analysis (e.g., Melan-A for melanoma)
  • Barrett’s esophagus progression to esophageal adenocarcinoma demonstrated in serial histology images

• Imaging and histopathology cues:

  • Apple-core appearance in colon cancer radiographs
  • Examples of benign vs malignant lesions via gross morphology, margins, and histology (lipoma, pleomorphic adenoma, ameloblastoma, osteosarcoma, rhabdomyosarcoma, mesothelioma, glioblastoma)

• Notable cancer types and examples:

  • Basal cell carcinoma: most common skin cancer; usually non-metastatic but locally invasive
  • Lung cancer (bronchogenic carcinoma): often aggressive; imaging may show lobulated masses
  • Mesothelioma: associated with asbestos exposure; causes lung compression and respiratory failure
  • Osteosarcoma and chondrosarcoma: bone and cartilage tumors
  • Rhabdomyosarcoma: malignant muscle tumor; varied histology
  • Colon cancer: colorectal adenocarcinoma described with apple-core lesion on imaging

• Key takeaways on cancer biology:

  • Cancer arises from a multi-step genetic and epigenetic process
  • Oncogenes and tumor suppressor genes govern the balance between proliferation and inhibition
  • Environmental and infectious factors significantly influence cancer risk
  • Early detection through screening improves prognosis
  • Metastasis dramatically worsens prognosis and dictates treatment strategy

Equations and Quantitative Highlights (LaTeX)

• Nernst potential for a given ion: E{ion} = \pm 61 \log{10}\left( \frac{Ci}{Co} \right) \text{ mV}
  • Example: EK \approx -94 \text{ mV}, \quad E{Na} \approx +61 \text{ mV}
• Goldman-Hodgkin-Katz equation (multi-ion resting potential):
  • Em = \frac{RT}{F} \ln\left( \frac{PK[K^+]o + P{Na}[Na^+]o + P{Cl}[Cl^-]i}{PK[K^+]i + P{Na}[Na^+]i + P{Cl}[Cl^-]_o} \right)
• Simple diffusion vs carrier-mediated transport can be summarized as:
  • Simple diffusion: D + (substrate) → DR (if carrier involved) or direct diffusion across lipid bilayer
  • Carrier-mediated (facilitated diffusion): saturable with maximum rate V_{max}
  • Active transport: energy-dependent (ATP), can be primary or secondary
• Dose-response conceptual formula (occupancy theory):
  • D + R ⇄ DR → Effect
• Pharmacodynamic terms:
  • Affinity: ability of a drug to bind receptor
  • Intrinsic activity (efficacy): ability of bound drug to activate receptor function
• Barrett’s esophagus progression (conceptual trajectory):
  • Normal squamous epithelium → intestinal metaplasia with goblet cells → dysplasia → carcinoma in situ → invasive adenocarcinoma

Quick Reference: Key Terms

• Membrane potential (MP)
• Resting membrane potential (RMP)
• Action potential (AP)
• Goldman equation / Nernst potential
• Ion channels: voltage-gated, ligand-gated, leak channels
• Saltatory conduction
• Nodes of Ranvier
• Schwann cells and myelination
• Neuromuscular junction (NMJ)
• Local anesthetic (LA) mechanism (e.g., lidocaine)
• Receptors: ion channel-linked, GPCRs, enzyme-linked, intracellular (nuclear)
• Agonist, antagonist, partial agonist
• Competitive vs noncompetitive antagonists
• Dose-response curve, ED50/EC50
• Occupancy theory and spare receptors
• Allosterism and allosteric sites
• Cancer biology: oncogenes, tumor suppressor genes, hallmarks of cancer
• Dysplasia, carcinoma in situ, invasion, metastasis
• Barrett’s esophagus, dysplasia progression
• Screening modalities: Pap smear, mammography, PSA, colonoscopy
• Common cancers by site and age/gender context (e.g., prostate, breast, lung, colorectal)
• Metastasis pathways: lymphatic, hematogenous, transcoelomic
• Viral etiologies: HPV, EBV
• Environmental and lifestyle risk factors: tobacco, alcohol, obesity, radiation

End of Notes