Vaidya saadhana: Reconsidering therapeutics in pharmacologically altered physiology

When the body tissues and sensory faculties are weakened, and the individual is exhausted, debilitated, hungry, or already affected by prior medication, further drug administration is not advisable.[1] Ayurveda perceives health not only as the absence of disease but also as an equipoise between physiological, psychological, and spiritual domains, which reflects through the balanced state of Dosha (~regulatory functional factors of the body), Agni (~digestive/metabolic factors), Dhatu (~major structural components of the body), Mala (~waste products), Mana (~psyche), Atma (~soul), and properly functioning Indriyas (~cognitive organs).[2] Acharya Charaka highlights that the success or failure of a treatment is determined not only by the drug but also by the physiological state of the body to receive and respond to it.[3] At present, contemporary health care is grappling with an increasing prevalence of excessive and often irrational drug administration, particularly in the form of injudicious polypharmacy.[4] Polypharmacy, self-medication, indiscriminate drug use, antibiotic overuse, chronic steroid use, and irrational supplementation frequently impair the body’s physiological resilience, leading to pervasive systemic dysregulation. Consequently, this leads to impaired metabolic adaptability, altered pharmacodynamic sensitivity, increased susceptibility to Adverse Drug Reactions (ADRs), abnormal immune response, microbiome dysbiosis, multiorgan dysfunction, and heightened iatrogenic risk among physiologically compromised individuals.[4,5] In such states, further drug administration may compromise the therapeutic benefits, shifting the trajectory from healing to harm. Acharya Kashyapa has acknowledged the potential jeopardy of inappropriate drug administration, wherein explicit contraindications are described based on both physiological and psychological states of the individual. Although these principles are described in Kashyapa Samhita (a foundational treatise on pediatric practice), their underlying rationale reflects broader pharmacotherapeutic prudence that may reasonably be extended beyond pediatric care to adult clinical practice. This cautious approach to drug administration is further supported in Charaka Samhita, wherein therapeutic administration is advised only after careful assessment of each individual’s physiological integrity, metabolic competence, psychological state, and disease condition.[3] Physiological conditions, including Ksheena dhatu-indriya (~tissue depletion and sensory weakness), Klanti (~exhaustion), Bubhuksha (~hunger), Ajirna (~indigestion), Karma atibhara abhihata (~excessive physical exertion), Abhakta (~fasting), Sadyo-peeta (~immediate food or water intake), Murchita (~unconsciousness), Gharma-tapita (~heat exposure), recent Panchakarma (~five major purification therapy) procedures, and Avastha viprita (~physiologically incompatible states), are considered unsuitable for therapeutic intervention. Similarly, psychological disturbances, including Krodha (~anger), Vishada (~depression), Shoka (~grief), and Ratri jagarana (~awakening till late night), are also recognized as conditions requiring therapeutic restraint. Among these, particular significance is accorded to the state of Bhaishajya dagdha koshtha, a condition in which the body has already been affected by prior medication exposure, underscoring caution regarding the administration of further therapeutics in pharmacologically compromised physiology.[1] THE BODY BEYOND A PASSIVE DRUG RECIPIENT Conventional pharmacology often conceives drug action in a linear manner, wherein a drug enters the body, interacts with a specific molecular target, and subsequently produces a predictable therapeutic response through defined pharmacodynamic mechanisms.[6] While this paradigm has enhanced the precision of drug development, it often overlooks the inherent physiological heterogeneity and adaptive complexity of biological systems. Contemporary evidence indicates that pharmacological intervention can modulate gene expression and receptor sensitivity, alter tissue integrity and organ reserve, influence physiological capacity and functional thresholds, affect neuroimmune and psychological responses, reshape metabolic pathways, and induce adaptive or maladaptive responses with repeated exposure. Consequently, the body may become physiologically distinct from its previous state.[7] In this context, Ayurveda offers a complementary perspective by recognizing the body as an active, dynamic determinant of therapeutic response, wherein Prakriti (~somatic constitution); physiological attributes such as Sara (~tissue excellence), Samhanana (~compactness), Pramana (~body proportionality), Vaya (~age), Agni, and Vyayama shakti (~physical capacity); psychological status (Satwa); Vikriti (~pathological state); and adaptive compatibility (Saatmya) play an integrative role in guiding therapeutic decision-making.[3] Therefore, repeated or inappropriate pharmacological exposure may progressively alter this homeostasis and amplify physiological dysfunction. RECONCEPTUALIZING KOSHTHA: A MULTILEVEL PHYSIOLOGICAL CONSTRUCT Koshtha in Ayurveda refers to the visceral cavity and the organs contained within it, primarily including Grahani (~duodenum), along with other major metabolic and vital organs such as the heart, liver, kidneys, and spleen, constituting the structural components, while Agni represents its principal functional component.[8,9]Koshtha is understood not only as an anatomical description of the gut but also as a dynamic internal milieu that governs digestion, transformation, metabolism, assimilation, and elimination of substances. The concept of Koshtha can be reconceptualized as a multilevel biological construct encompassing interconnected domains, ranging from cellular metabolism to systemic integration [Figure 1]. Drug exposure can alter these domains across multiple levels, reducing physiological resilience and predisposing to adverse outcomes, thereby transforming it into a functionally compromised physiological state.Figure 1: Koshtha as a multilevel physiological constructBHAISHAJYA DAGDHA KOSHTHA: BIOLOGICAL CONSEQUENCES OF PHARMACOLOGICAL STRESS From an Ayurvedic standpoint, the multilevel biological consequences of Bhaishajya dagdha koshtha may be understood as progressive derangement of Agni, Dhatu, Strotas (~structural or functional channels), and systemic homeostasis. These alterations may be understood in terms of their modern biological counterparts at the molecular, cellular, organ, and system levels. MOLECULAR LEVEL At the molecular level, chronic pharmacological stress modulates drug metabolism-related enzymatic systems via induction or inhibition of cytochrome P450 activity, impaired Phase II detoxification pathways, depletion of glutathione reserves, and altered renal clearance.[10] These alterations directly influence the metabolic capacity and precipitate the accumulation of reactive intermediates and toxic metabolites, functionally similar to the concept of Ama (~toxic byproduct generated due to improper or incomplete digestion), disrupting physiological equilibrium and predisposing adverse reactions upon further drug administration. CELLULAR LEVEL Many drugs inadvertently dysregulate the functions of mitochondria in the enterocytes and hepatocytes by interfering with the electron transfer chain, increasing the production of Reactive Oxygen Species (ROS), damaging mitochondrial Deoxyribonucleic Acid (DNA) and reduced Adenosine Tri-Phosphate (ATP) synthesis that leads to cellular injury. ROS produced during the injury further depletes the antioxidant reserve and activate apoptotic mechanisms, ultimately contributing to progressive inflammation.[11] In Ayurvedic parlance, these alterations may be interpreted as impairment of Dhatvagni (~metabolic factors located in Dhatu), leading to compromised cellular vitality and progressive tissue dysfunction. ORGAN LEVEL Irrational drug administration can have a deleterious effect on the functional integrity of key organs, particularly the gastrointestinal tract, liver, and kidneys, which are primarily involved in metabolism and elimination. Prolonged use of medications, such as the Non Steroidal Anti-Inflammatory Drugs (NSAIDs), steroids, chemotherapeutic agents, antipsychotic drugs, and antibiotics, disrupt the gut lining, modify the epithelial permeability, and cause dysbiosis, leading to an array of drug-induced disorders.[12] Repeated drug administration may start a vicious cycle, whereby the initial drug modifies the microbiota that leads to oxidative stress, which in turn modifies future drug metabolism. Drug-Induced Liver Injury (DILI) is the most common among metabolism-mediated organ toxicities, whereby the hepatic injury occurs not only due to the drug dose but also due to compromised hepatic function caused by prior medication, chronic inflammation, malnutrition, oxidative stress, and/or systemic illness.[13] Similarly, nephrotoxicity precipitates in physiologically disrupted kidneys, where dehydration, hypoperfusion, prior nephrotoxic exposure, or reduced glomerular filtration impair drug clearance and promote toxic accumulation.[14] Through the Ayurvedic lens, these alterations may be correlated with Srotodushti (~deformity in the body channels), wherein disruption of the structural and functional channels impairs the normal processes of transformation, transport, and elimination within the body, thereby contributing to broader physiological imbalance and increased susceptibility to ADRs. SYSTEM LEVEL At the system level, pharmacological perturbations influence the gut–brain–immune axis via interconnected neuronal, endocrinal, immunological, and microbial pathways. Impaired gut lining and microbial flora can alter vagal signaling, thereby precipitating inflammatory response through amplified cytokine release, increased intestinal permeability causing translocation of endotoxins and microbial products into circulation, disruption of bidirectional gut–microbiome communication further precipitating dysbiosis, and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic balance.[15] Certain drugs, such as glucocorticoids, opioids, and Selective Serotonin Reuptake Inhibitors (SSRIs), modulate the HPA axis and aberrantly regulate the immune response, thereby contributing to persistent neuroimmune and metabolic alterations that affect physiological adaptability and susceptibility to ADRs.[16] Collectively, these multilevel alterations diminish physiological resilience, disrupt homeostasis, and render the internal milieu more susceptible to adverse reactions. Under these circumstances, further drug administration may surpass the adaptive capacity of the body, shifting the course from therapeutic gain to unintended harm. In essence, in the present era of polypharmacy, self-medication, and irrational therapeutic practices, this aphorism offers a translational framework that may help understand vulnerable physiological states at increased risk of ADRs, therapeutic failure, cumulative toxicity, and multiorgan dysfunction. The verse may be understood as emphasizing the necessity of evaluating the body’s therapeutic tolerance and systemic preparedness before drug administration, particularly in states of compromised Agni, Dhatu, Bala (~immunity), and Ojas (~essence of all seven Dhatu). This understanding resonates with the classical Ayurveda principle of “Purusham purusham veekshya,” which advocates thorough assessment of the individual before therapeutic intervention.[17] Accordingly, management strategies in such conditions should incorporate measures aimed at strengthening Agni, supporting gut integrity, correcting Srotodushti, improving nutritional status, preserving Ojas, and enhancing physiological resilience, thereby reinforcing a shift from reflexive drug escalation toward individualized, safety-oriented therapeutic decision-making aimed at preventing iatrogenic harm. Authors’ contributions D.D. conceptualized the review, conducted the literature search, and prepared the original draft of the manuscript. A.R. critically reviewed and revised the manuscript for important intellectual content. Both authors contributed to manuscript refinement and approved the final version. Data availability No new data were generated in this study. All information discussed in this review is derived from previously published sources cited in the manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.