What are the fundamental principles of pharmacology, including drug nature and sources, routes of administration, drug absorption and bioavailability, and drug distribution?

Fundamental Principles of Pharmacology: Drug Nature, Routes of Administration, Absorption, and Distribution

The understanding of drug pharmacokinetics and pharmacodynamics is essential for effective therapeutic outcomes, with absorption, bioavailability, and distribution being critical factors that determine a drug's efficacy and safety profile.

Drug Nature and Sources

• Drugs can be classified based on their chemical structure, mechanism of action, and biological source (natural, semi-synthetic, or synthetic) 1
• Primary pharmacodynamic studies investigate the mechanism of action and effects of substances in relation to their desired therapeutic targets, typically conducted during the discovery phase of pharmaceutical development 1
• Secondary pharmacodynamic studies examine the "off-target" effects of drug candidates unrelated to their desired therapeutic target, which are particularly important for small molecules but less relevant for highly specific biopharmaceuticals 1

Routes of Administration

• The least invasive method of drug administration should be used whenever possible, with oral administration being preferable due to convenience and relatively steady blood concentrations 1
• Different routes of administration include oral, subcutaneous, intravenous, transdermal, sublingual, intrathecal, and rectal, each with specific advantages and limitations 1
• Intravenous administration provides the most rapid onset and shortest duration of action but requires more technical skill and monitoring than oral administration 1
• Subcutaneous and intramuscular injections have disadvantages including wider fluctuations in absorption and more rapid fall-off of action compared to oral administration 1

Drug Absorption and Bioavailability

• Absorption is defined as the movement of a drug across the outer mucosal membranes of the gastrointestinal tract, while bioavailability refers to the availability of the drug to the general circulation or site of pharmacological actions 2
• Oral bioavailability specifically refers to the rate and extent to which an active drug substance is absorbed and becomes available to the general circulation 3
• Drug absorption is influenced by several factors including drug solubility, permeability, and the rate of in vivo dissolution 4
• The Biopharmaceutics Classification System is an important tool for predicting compounds likely to be associated with bioavailability problems and identifying factors that may alter drug absorption 4

Factors Influencing Drug Absorption and Bioavailability

Physiological Factors

• Age-related changes affect drug disposition, metabolism, and responses to analgesic medications, with older patients generally at higher risk of adverse drug reactions 1
• Sex-related differences in pharmacokinetics arise from physiological differences in body composition, organ function, and hormonal changes 1
• Women have higher proportion of body fat but lower body weight/size, muscle mass, organ sizes, plasma volume, cardiac output, and organ blood flow compared to men, affecting drug distribution 1
• Pregnancy can alter drug metabolism, with increased activity of certain cytochrome P450 enzymes (CYP1A2, 2C9, 2D6, 3A4) but decreased activity of others (CYP2C19) 1

Drug-Related Factors

• Lipophilic drugs have faster onset, higher volume of distribution, and longer duration of action in women due to their higher proportion of body fat 1
• Hydrophilic drugs reach higher peak plasma levels in women due to smaller volume of distribution 1
• Administration with a high-fat meal can significantly increase oral cannabinoid absorption and may exacerbate drug effects 1
• Drug formulation and pharmaceutical factors such as particle size, crystal form, and excipients can affect dissolution rate and subsequent absorption 4

Metabolic and Enzymatic Factors

• Hepatic clearance is influenced by cardiac output, liver blood flow (both lower in women), and the activity of drug metabolizing enzymes and transporters 1
• Women present increased activity of cytochromes P450 (CYP) 3A4 and 2D6 but reduced activity of the transporter P-glycoprotein (P-gp) 1
• Cannabis and cannabinoids can inhibit various cytochrome P450 enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19), potentially leading to drug-drug interactions 1
• The potential for drug-drug interactions through altered metabolism pharmacokinetics should be carefully considered, especially with drugs having narrow therapeutic indices 1

Drug Distribution Throughout the Body

• Drug distribution depends on body composition, plasma volume, organ blood flow, and tissue and plasma protein binding 1
• Volume of distribution (Vd) is an important parameter that affects drug concentration at target sites 1
• Most cannabinoids, including THC, are highly lipid soluble, resulting in adipose tissue accumulation which can lead to gradual release of stored drug after periods of adipose breakdown 1
• Pharmacodynamically, in vivo bacterial killing may be described as a function of the duration of antimicrobial drug concentration over time relative to the MIC of that agent against a particular pathogen 1

Pharmacokinetic/Pharmacodynamic Principles

• Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of drugs, while pharmacodynamics describes the relationship between drug concentration and pharmacologic effect 1
• The area under the curve (AUC) represents the product of drug concentration and time of drug exposure in the bloodstream over the dosing interval 1
• Outcome of infection in animal models and human studies usually correlates with one of three pharmacodynamic parameters: time above the MIC, ratio of peak serum concentration to MIC, or ratio of AUC to MIC 1
• Tolerance, physical dependence, and hyperalgesia are characteristics of repeated opioid administration that are affected by the potency, route of administration, latency of onset, and analgesic duration of the particular opioid 1

Special Considerations

• Dosing for most patients requires initiation with low doses followed by careful upward titration, including frequent reassessment for dosage adjustments and optimum relief 1
• The "start low, go slow" approach is particularly important for cannabis and cannabinoids due to potential side effects such as euphoria, drowsiness, dizziness, vertigo, and hallucinations 1
• Women have lower renal blood flow, estimated glomerular filtration rate (eGFR), and tubular secretion/reabsorption than men, resulting in slower clearance of drugs primarily excreted unchanged in urine 1
• Administration of the same doses in women and men frequently results in higher drug exposure in women, leading to a higher incidence of adverse drug reactions 1