WHMF221 – Herbal Pharmacology & Pharmacognosy: Comprehensive Bullet-Point Notes

Herbal Actions and Mechanisms

• Herbal constituents are bio-active molecules that, like pharmaceutical drugs, interact with biological systems (cells, tissues, organs, whole organism).

  • The specific cells/tissues a constituent contacts determine its observable effects.
  • Measurable organism-level outcomes arise from cumulative cellular responses.

• Scientific domains informing modern research on herbal MoA (mechanisms of action):

  • Biochemistry → molecular interactions & enzyme kinetics.
  • Systems biology (multi-omics) → holistic mapping from genes to metabolites.
  • Network pharmacology → computational mapping of multi-target, multi-compound interactions.

Systems Biology & Network Pharmacology

• Systems biology principles

  • Inter-disciplinary (biology + physics + maths + computer science + engineering).
  • Integrates information across hierarchical levels: molecule → cell → tissue → organ → organism.
  • Employs “omics” technologies:
  • Genomics (DNA), Epigenomics (methylation, histone mods) → gene regulation.
  • Transcriptomics (mRNA) → transcriptional activity.
  • Proteomics (proteins/enzymes) → functional effectors.
  • Metabolomics (small-molecule metabolites) → pathway outputs.
  • Microbiomics → microbial genomes influencing host biochemistry.

• Network pharmacology

  • An emergent field (early-2000s) analysing drug actions on multiple targets simultaneously.
  • Integrates large bioinformatic datasets (omics, clinical, chemical libraries).
  • Utilises machine-learning & graph theory to:
  • Identify target ‘hubs’ & pathways.
  • Predict synergy/antagonism between constituents.
  • Visualise herb-constituent–target–disease networks.
  • Complexity illustration: One formula (multi-herb) → many constituents → dozens of targets → multiple disease pathways.

Pharmacology Fundamentals

Pharmacodynamics (PD) — “what the drug does to the body”

• Process
  • Substance is present in system → binds a molecular target → triggers/blocks a biological response → system adapts (observable effect).
• Signal transduction pathways underpin PD responses
  • Cascades of protein interactions (receptors, kinases, phosphatases, transcription factors).
  • Regulate growth, metabolism, immunity, survival, etc.
  • Common pathway groups & exemplar mediators:
  • Cellular defence: Nrf2, NF-κB, MAPK, Toll-like receptors (TLRs).
  • Cell-cycle: p53, EGFR/PDGFR, CDKs.
  • Survival/apoptosis: PI3K/Akt, caspases, Bcl-2 family.
  • Metabolic: AMPK, mTOR, PPARs.
  • Immune: JAK/STAT, T- & B-cell receptors.
• Example pathway (Martel et al. 2020)
  • Detrimental bacteria → LPS → TLR-4 → IKK → IκBα degradation → NF-κB activation → Pro-inflammatory gene transcription → Inflammation.
  • Phytochemicals (capsaicin, curcumin, resveratrol, silibinin) modulate nodes (e.g., inhibit IKK, scavenge ROS) → anti-inflammatory outcome.

Structure-Activity Relationship (SAR)

• Drug–target affinity analogous to lock-and-key (or combination lock):
  • Shape, charge, hydrophobicity of ligand dictate docking.
  • Molecular docking software predicts optimal binding poses.
• Herbal example: Flavonoids binding P-glycoprotein (P-gp)
  • Specific hydroxyl/methoxy positions critical (key “cuts”).
  • Influences absorption/efflux of many xenobiotics.

Pharmacodynamic Terminology

Pharmacokinetics (PK) — “what the body does to the drug”

\text{ADME} = {\text{Absorption},\;\text{Distribution},\;\text{Metabolism},\;\text{Elimination}}

Absorption

• Routes into enterocyte: passive diffusion, facilitated diffusion, active transport, endocytosis.
• Modifiers:
  • Metabolism before absorption (phase I/II enzymes, microbiota).
  • Efflux transporters (e.g., P-gp) pump drug back to lumen, lowering bioavailability.
• Brush-border synergy: Co-constituents may open tight junctions, inhibit P-gp, package actives in natural nanoparticles, raising uptake.

Distribution

• Reversible movement via bloodstream/lymph.
• Protein-bound fraction = pharmacologically inactive; only free drug exerts effect.

Metabolism (Biotransformation)

• Goal: Increase polarity → facilitate excretion.
• Carried out by CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 3A4, etc.) located mainly in liver, also gut, kidney, brain.
• Influencing factors: genetics, inflammation, sex, age, diet, other drugs.
• Microbial metabolism
  • Gut flora convert phytochemicals into smaller or novel metabolites; antibiotics disrupt this, changing PK (e.g., baicalin → baicalein-6-glucuronide levels drop in antibiotic-treated rats).

Elimination

• Routes: faeces, urine, exhaled air, sweat, hair/skin/nails, menstrual blood.
• Entero-hepatic recirculation
  • Conjugated metabolites excreted in bile → gut → microbial de-conjugation → reabsorption → prolonged half-life.

Factors Influencing PK

• Species, sex, age, disease state, concomitant drugs, route/formulation, dose.

Herbal Synergy

• Definition: Combined effect greater (or occasionally lesser) than sum of individual effects.
• Mechanistic categories (Che et al. 2013):
  • Reinforcement (mutual augmentation).
  • Potentiation (principal + adjunct).
  • Restraint/Detoxification (toxicity mitigation).
  • Counteraction (one herb reduces effect of another).
• Quantitative visual (isobologram):
  • Synergistic curve bows below additivity line; antagonism bows above.
• Molecular bases of synergy
  • Multi-pathway targeting, enhanced absorption, metabolic protection, signal amplification.
• Example: ADAPT-232 (Rhodiola + Eleutherococcus + Schisandra)
  • Mixture deregulates 261 unique genes absent in single-herb profiles → emergent properties.

Herb–Drug Interactions (HDIs)

• Grapefruit (Citrus paradisi)
  • Furanocoumarins irreversibly inhibit intestinal \text{CYP3A4} → ↓ first-pass metabolism → ↑ plasma drug levels for up to 24 h (new enzyme synthesis required).
• St John’s Wort (Hypericum perforatum)
  • Hyperforin activates Pregnane X Receptor → induces \text{CYP3A4} & P-gp → ↓ drug absorption & ↑ metabolism → reduced efficacy of OCPs, immunosuppressants, antivirals, etc.
  • Note: Hyperforin content declines with extract age → interaction potential diminishes.
• Practical workflow: Always consult HDI databases; document interactions in patient charts.

Herbal Energetics – Six Tissue States (Western physiomedicalism)

• Axes & Opposites
  • Temperature: Hot ↔ Cold
  • Moisture/Density: Damp ↔ Dry
  • Tone: Tense ↔ Relaxed
• Therapeutic aim: Apply herbs with opposite qualities to restore balance.
• Alignment with Ayurvedic Doṣas (Vata/Pitta/Kapha) offers integrative insight.

Case Example – Zingiber officinale (Ginger)

• Qualities: Hot, Dry, Stimulating, Dispersing.
• Mechanisms underpinning ‘heating’ sensation:
  • Activates TRPV1 (vanilloid) receptors → ↑ noradrenaline release.
  • Noradrenaline up-regulates Uncoupling Protein-1 (UCP-1) in mitochondria → thermogenesis.
• Clinical observations:
  • Infra-red imaging shows peripheral vasodilation & ↑ skin temperature post-ginger beverage.

Summary Key Take-aways

• Herbal pharmacology integrates molecular specifics (SAR, receptor binding) with systems complexity (multi-omics, microbiome, synergy).
• Pharmacodynamics explain mechanism, pharmacokinetics explain movement; both shape clinical outcomes.
• Signal transduction pathways provide numerous potential phytochemical targets, enabling diverse therapeutic actions.
• Synergy—within an herb, between herbs, or with drugs—can amplify efficacy or produce unintended interactions.
• Personalised practice requires understanding tissue energetics, patient-specific PK modifiers, and vigilant HDI monitoring.