Pharmacokinetics and Pharmacodynamics in Clinical Practice

 

Pharmacokinetics and Pharmacodynamics in Clinical Practice: A Comprehensive Guide for Internal Medicine

Dr Neeraj Manikath , claude.ai

Abstract

Understanding pharmacokinetics (PK) and pharmacodynamics (PD) is fundamental to rational prescribing and optimizing therapeutic outcomes in internal medicine. Despite their critical importance, these concepts are often poorly integrated into clinical practice. This review provides a comprehensive, clinically-oriented approach to PK/PD principles, emphasizing practical applications, common pitfalls, and evidence-based strategies for drug dosing in complex medical patients.

Introduction

The gap between pharmacological theory and bedside practice remains a persistent challenge in internal medicine. While medical students learn PK/PD principles in pharmacology courses, the translation of these concepts into clinical decision-making is often inadequate. This disconnect contributes to medication errors, adverse drug events, and suboptimal therapeutic outcomes. Approximately 30% of hospital admissions in elderly patients are related to adverse drug reactions, many of which are preventable with appropriate PK/PD understanding.

This review aims to bridge the theory-practice gap by providing a structured approach to applying PK/PD principles in everyday clinical scenarios, with particular emphasis on special populations and complex therapeutic situations commonly encountered in internal medicine.

Pharmacokinetic Principles: Beyond ADME

Absorption and Bioavailability

The journey of a drug begins with absorption, yet this process is frequently oversimplified in clinical teaching. First-pass metabolism can reduce oral bioavailability dramatically for certain drugs. For instance, propranolol undergoes extensive first-pass metabolism, resulting in only 25% bioavailability, necessitating higher oral doses compared to intravenous administration.

Clinical Pearl: In patients with liver cirrhosis and portosystemic shunting, drugs with high first-pass metabolism (propranolol, morphine, verapamil) achieve unexpectedly high plasma concentrations when given orally, increasing toxicity risk. Consider starting with 50% of standard doses and titrating carefully.

Drug absorption is profoundly affected by gastrointestinal physiology. Critically ill patients with decreased splanchnic perfusion, those on vasopressors, or patients with gastroparesis may have unpredictable oral drug absorption. This explains why oral antibiotics may fail in severe sepsis despite appropriate spectrum coverage.

Practical Hack: For drugs requiring reliable absorption in critically ill patients (antiepileptics, antibiotics, immunosuppressants), strongly consider parenteral routes initially, transitioning to oral only after hemodynamic stabilization.

Distribution: Volume of Distribution as a Clinical Tool

Volume of distribution (Vd) represents the theoretical volume into which a drug distributes in the body. This parameter has profound clinical implications often underappreciated at the bedside.

Hydrophilic drugs (aminoglycosides, vancomycin) have small Vd values (0.25-0.7 L/kg) and distribute primarily in extracellular fluid. In contrast, lipophilic drugs (amiodarone, digoxin) have large Vd values (multiple L/kg), distributing extensively into tissues.

Clinical Application: Loading doses depend directly on Vd. For digoxin (Vd approximately 500 L in a 70 kg patient), loading doses of 0.75-1.5 mg are needed to achieve therapeutic concentrations rapidly, despite maintenance doses of only 0.125-0.25 mg daily. Without loading, steady-state would require 7-10 days given digoxin's long half-life.

In patients with significant fluid shifts (sepsis, heart failure, burns), the Vd of hydrophilic drugs increases substantially. This necessitates higher initial doses of drugs like vancomycin and aminoglycosides to achieve therapeutic concentrations. Studies have demonstrated that critically ill patients may require vancomycin loading doses of 25-30 mg/kg compared to standard 15-20 mg/kg dosing.

Oyster: Obesity paradoxically affects Vd differently for various drugs. While lipophilic drugs might be expected to have increased Vd in obesity, adipose tissue is poorly perfused, and many lipophilic drugs preferentially distribute to well-perfused lean tissues. Consequently, dosing based on total body weight may lead to overdosing. For drugs like propofol and lipophilic benzodiazepines, consider using adjusted body weight or lean body weight for dosing calculations.

Metabolism and the Cytochrome P450 System

The CYP450 enzyme system metabolizes approximately 75% of all drugs. Understanding CYP450-mediated interactions is essential for preventing adverse events and therapeutic failures.

Common CYP450 Interactions in Internal Medicine:

• CYP3A4 inhibitors (clarithromycin, diltiazem, grapefruit juice) increase concentrations of statins, leading to rhabdomyolysis risk
• CYP2C9 inhibitors (amiodarone, fluconazole) potentiate warfarin, increasing bleeding risk
• CYP1A2 inducers (smoking) decrease theophylline and clozapine concentrations

Clinical Pearl: When initiating or discontinuing CYP450 inhibitors or inducers, the time to maximal effect depends on the half-life of the affected drug. For warfarin (half-life 40 hours), significant changes in INR may not appear for 3-5 days after starting an interacting drug. Anticipate this lag and monitor accordingly.

Genetic polymorphisms in CYP450 enzymes create significant interpatient variability. CYP2C19 poor metabolizers (2-5% of Caucasians, up to 20% of Asians) have reduced activation of clopidogrel, potentially increasing cardiovascular events post-stenting. Pharmacogenetic testing is increasingly available and should be considered for patients with unexpected drug responses.

Elimination and Renal Function

Renal elimination is the primary clearance mechanism for many drugs in internal medicine. The Cockcroft-Gault equation or CKD-EPI equation estimates glomerular filtration rate (GFR), but these have significant limitations in certain populations.

Practical Considerations:

• Cockcroft-Gault overestimates GFR in obesity and underestimates in cachexia
• Both equations are unreliable in acute kidney injury with rapidly changing serum creatinine
• Elderly patients with sarcopenia may have significantly reduced GFR despite "normal" serum creatinine due to decreased creatinine production

Clinical Hack: For drugs with narrow therapeutic indices requiring renal dose adjustment (vancomycin, aminoglycosides, direct oral anticoagulants), consider therapeutic drug monitoring or more conservative dosing in patients with borderline renal function, particularly elderly individuals.

Hepatic elimination follows either first-order (most drugs) or zero-order kinetics. Drugs following zero-order kinetics (phenytoin, aspirin at high doses, ethanol) saturate elimination pathways, causing disproportionate increases in plasma concentrations with small dose increases.

Oyster: Phenytoin exhibits zero-order kinetics at therapeutic concentrations. A seemingly small dose increase from 300 mg to 400 mg daily may cause plasma concentrations to increase from therapeutic to toxic range, precipitating ataxia and altered mental status. When adjusting phenytoin doses, increase by no more than 30-50 mg increments and monitor levels closely.

Pharmacodynamic Principles: Translating Concentration to Effect

Concentration-Effect Relationships

Pharmacodynamics describes the relationship between drug concentration and pharmacological effect. This relationship is characterized by the dose-response curve, typically sigmoidal in shape.

Key PD Parameters:

• EC50: concentration producing 50% of maximal effect
• Emax: maximum achievable effect
• Potency: concentration required to produce a given effect
• Efficacy: maximum effect achievable

Clinical Application: Understanding the shape of the dose-response curve prevents futile dose escalation. For drugs on the plateau portion of their dose-response curve, further dose increases produce minimal additional benefit while increasing toxicity risk. Beta-blockers for heart rate control exemplify this principle; increasing metoprolol from 200 mg to 400 mg daily rarely provides additional heart rate reduction but increases side effect risk.

Time-Dependent vs Concentration-Dependent Killing

Antimicrobial pharmacodynamics has revolutionized antibiotic dosing strategies. Antibiotics exhibit either time-dependent or concentration-dependent killing characteristics.

Time-dependent antibiotics (beta-lactams, vancomycin) require drug concentrations above the minimum inhibitory concentration (MIC) for a certain percentage of the dosing interval. For beta-lactams, optimal bactericidal activity occurs when concentrations remain above MIC for 40-70% of the dosing interval depending on the specific agent. This principle supports extended or continuous infusions of beta-lactams in critically ill patients with augmented renal clearance or difficult-to-treat infections.

Concentration-dependent antibiotics (aminoglycosides, fluoroquinolones, daptomycin) achieve maximal bacterial killing when peak concentrations substantially exceed the MIC. The peak:MIC ratio predicts efficacy. This supports once-daily aminoglycoside dosing, which produces higher peak concentrations, enhanced bacterial killing, and potentially reduced nephrotoxicity compared to traditional multiple daily dosing.

Clinical Pearl: For severe pseudomonal infections, consider extended infusion piperacillin-tazobactam (4.5 g infused over 4 hours every 8 hours) rather than standard 30-minute infusions. This maintains concentrations above MIC for a greater percentage of the dosing interval, potentially improving outcomes in critically ill patients.

Special Populations and Physiological Alterations

Elderly Patients

Aging profoundly affects both PK and PD parameters. Physiological changes include decreased hepatic blood flow, reduced CYP450 activity, diminished renal function, decreased total body water, increased body fat, and reduced plasma albumin.

These changes increase the half-life of many drugs and enhance sensitivity to drug effects. The Beers Criteria identify potentially inappropriate medications in older adults based on unfavorable PK/PD profiles in this population.

Practical Approach: For elderly patients, "start low and go slow" is more than a cliché. Consider initiating drugs at 50% of standard adult doses for renally eliminated drugs, central nervous system agents, and drugs with narrow therapeutic indices. The adage "no dose is too low to start, but there's always a dose too high" applies particularly to geriatric medicine.

Obesity

Obesity alters Vd, clearance, and PD responses in complex, drug-specific ways. No universal dosing adjustment applies across all medications.

General Principles:

• Hydrophilic drugs: dose based on ideal body weight or adjusted body weight
• Lipophilic drugs: varies by specific agent and clinical context
• Drugs with significant protein binding: consider increased Vd in obesity

Clinical Example: Enoxaparin dosing in obesity remains controversial. Current evidence suggests dosing obese patients (BMI >40 kg/m²) based on total body weight up to a maximum of 150 mg subcutaneously twice daily for treatment doses, with anti-Xa monitoring to ensure therapeutic range achievement.

Critical Illness

Critical illness profoundly disrupts normal PK/PD relationships through multiple mechanisms including altered protein binding, increased Vd, augmented renal clearance, and organ dysfunction.

Augmented renal clearance (ARC), defined as creatinine clearance exceeding 130 mL/min, occurs in 30-65% of critically ill patients, particularly younger trauma victims and burn patients. ARC increases elimination of renally cleared drugs, potentially causing subtherapeutic concentrations with standard dosing.

Practical Hack: Suspect ARC in young critically ill patients with low or low-normal serum creatinine despite absent or minimal urine output documentation. For these patients receiving renally eliminated antibiotics, consider higher doses or therapeutic drug monitoring to ensure adequate concentrations.

Renal and Hepatic Impairment

Chronic kidney disease and cirrhosis necessitate dosing adjustments for many medications, but the approaches differ fundamentally.

For renal impairment, dose reductions typically involve decreasing individual doses, extending dosing intervals, or both. Reference resources provide specific recommendations based on estimated GFR. Critical considerations include avoiding nephrotoxic drugs when possible and recognizing that drug metabolites may accumulate even when parent drug clearance seems adequate.

For hepatic impairment, dose adjustment is less standardized. Child-Pugh score provides some guidance, but no universal approach exists. Generally, drugs undergoing extensive hepatic metabolism require dose reduction in cirrhosis, and drugs highly protein-bound may have enhanced free fraction due to hypoalbuminemia.

Oyster: Hepatic metabolism involves both Phase I (CYP450-mediated) and Phase II (conjugation) reactions. Cirrhosis impairs Phase I reactions more than Phase II reactions. Therefore, drugs metabolized primarily through glucuronidation (lorazepam, oxazepam) may be preferable to those requiring CYP450 metabolism (diazepam, midazolam) in patients with advanced liver disease.

Therapeutic Drug Monitoring: When and How

Therapeutic drug monitoring (TDM) is essential for drugs with narrow therapeutic indices where the difference between therapeutic and toxic concentrations is small. Commonly monitored drugs in internal medicine include vancomycin, aminoglycosides, digoxin, phenytoin, valproic acid, lithium, and immunosuppressants.

Principles of Effective TDM:

1. Understand sampling timing: trough levels are drawn immediately before the next dose, while peak levels depend on the specific drug and administration route
2. Ensure steady-state: most drugs require 4-5 half-lives to reach steady-state; sampling before steady-state yields misleading results
3. Interpret results in clinical context: therapeutic ranges are population-based guidelines, not absolute rules

Clinical Pearl: For vancomycin, the area under the curve to MIC ratio (AUC/MIC) predicts efficacy and nephrotoxicity better than trough-based monitoring. Emerging evidence supports Bayesian dosing software to estimate AUC rather than relying solely on trough concentrations. Target AUC/MIC ratios of 400-600 for most serious infections.

Pharmacogenomics in Clinical Practice

Pharmacogenomics is transitioning from research curiosity to clinical tool. Genetic variations affecting drug metabolism, transport, and targets can profoundly influence therapeutic responses.

Clinically Actionable Pharmacogenomic Tests:

• HLA-B*5701 testing before abacavir (prevents hypersensitivity reactions)
• TPMT testing before azathioprine or mercaptopurine (prevents severe myelosuppression)
• CYP2C19 genotyping for clopidogrel (identifies poor metabolizers at increased cardiovascular risk)
• G6PD testing before oxidant drugs (prevents hemolytic anemia)

While universal preemptive pharmacogenomic testing remains debated, targeted testing for specific clinical scenarios is increasingly standard of care.

Conclusion

Mastery of PK/PD principles transforms prescribing from empiric guesswork to rational, individualized therapy. By understanding how drugs move through the body and produce effects, clinicians can anticipate drug interactions, adjust doses appropriately for special populations, optimize timing of therapeutic drug monitoring, and recognize adverse events earlier.

The key is integrating these principles into daily clinical reasoning rather than treating them as abstract pharmacology concepts. Every prescription should prompt consideration of patient-specific factors affecting PK/PD: age, weight, organ function, concomitant medications, genetic factors, and disease state.

As precision medicine advances, PK/PD principles will become even more central to optimal therapeutics. Clinicians who develop fluency in these concepts will be better equipped to navigate increasingly complex pharmacotherapy and deliver truly personalized medical care.

References

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