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Principles of Pharmacology – Week 3 Seminar Notes

Pharmacokinetics: Overview

  • Pharmacokinetics is the movement of drugs inside the body; describes the physiological processes acting on a drug after it enters the body (i.e., how the body handles a drug).
  • Four key processes:
    • Absorption: how the drug enters the body
    • Distribution: where the drug goes in the body
    • Metabolism: how the drug is broken down
    • Excretion: how the drug leaves the body
  • These processes determine the drug's clinical response (efficacy) and potential adverse effects (toxicity).
  • Drug journey involves various compartments: drug in systemic circulation, tissue reservoirs, free vs bound drug, metabolites (active and inactive), and protein-bound drug.
  • Relevance to pharmacology: links between pharmacokinetics (PK) and pharmacodynamics (PD), including receptor interactions and tissue distribution.

Absorption

  • Routes of absorption include:
    • Oral
    • Rectal
    • Sublingual
    • Injectable (not IV)
    • Transdermal
    • Topical
    • IV is not an absorption process per se (IV bypasses absorption).
  • Post-oral administration sequence:
    1) Drug absorbed into the tissues of the wall of the small intestine
    2) Moves across walls of interstitial blood vessels into the bloodstream
  • Cell membrane characteristics (from structural biology):
    • Hydrophobic (water-repelling) vs Hydrophilic (water-loving) membranes influence drug passage
    • Lipid solubility affects crossing of phospholipid membranes
  • Mechanisms of drug absorption across membranes:
    • Passive diffusion: energy-free, down a concentration gradient; favored by lipid-soluble drugs
    • Filtration: energy-free, pressure-driven movement through pores; depends on molecular size/weight
    • Active transport: requires energy; against concentration gradient
    • Facilitated diffusion: carrier-mediated, down concentration gradient; energy-free
  • Important points influencing absorption (non-IV routes):
    • Physiochemical properties:
    • Physical state: liquids absorbed better than solids
    • Particle size: smaller particles absorbed better
    • Disintegration time: time to disintegrate into fine particles
    • Dissolution time: time to dissolve into solution
    • Lipid solubility: lipid-soluble drugs cross membranes more easily
    • pH and ionisation:
    • Ionised drugs are poorly absorbed; unionised drugs are lipid soluble and better absorbed
    • Degree of ionisation depends on the medium’s pH (acidic drugs remain un-ionised in acidic medium; basic drugs in alkaline medium)
    • Absorbing surface area and vascularity: larger area and greater blood flow → better absorption
    • Gastrointestinal motility: gastric emptying time and intestinal motility
    • Faster gastric emptying → faster reaching intestine and absorption
    • Faster intestinal motility → reduced contact time → reduced absorption
    • Presence of food: can slow gastric emptying and dilute the drug or form drug-food complexes that are incompletely absorbed
  • pH effects on absorption (illustrative):
    • Acidic drugs are less ionised in acidic environments and more lipophilic, influencing absorption depending on site and surface area
  • Example question (theory):
    • Aspirin absorption: although aspirin is acidic and less ionised in the stomach, most absorption occurs in the small intestine due to larger surface area and prolonged contact time in the intestine

Distribution

  • After absorption, distribution involves movement of drug from systemic circulation to tissues and sites of action; includes crossing barriers and interacting with tissue components
  • Routes of distribution are not uniform; factors include:
    • Water-soluble drugs remain largely in plasma
    • Fat-soluble drugs distribute into adipose tissue stores
    • Distribution is proportional to regional blood flow (higher blood flow → greater drug delivery to that area)
  • Key determinants of distribution:
    • Lipid solubility
    • Ionisation
    • Vascularity
    • Binding to plasma and cellular proteins
    • Tissue characteristics (perfusion, lipid content, pH, membrane permeability)
  • Plasma protein binding (PPB):
    • Drugs may bind to plasma proteins in systemic circulation; only free (unbound) drug is available for action, metabolism, and excretion
    • Bound drug acts as a reservoir; when free drug concentration falls, bound drug can dissociate and replenish the free pool
  • Clinical significance of PPB:
    • High PPB affinity can increase drug half-life and duration of action
    • Co-administered drugs may compete for the same protein-binding sites, potentially displacing another and increasing the free fraction (toxicity risk)
    • Saturation of binding sites can occur with repeated dosing
    • Renal failure or chronic hepatic dysfunction can decrease plasma proteins, increasing free drug fraction
  • Blood-brain barrier (BBB):
    • BBB protects the brain from noxious substances; specialized endothelial cells form a barrier between capillaries and brain tissue
    • Only highly lipophilic substances or those actively transported can pass into CNS; glial cells provide additional protection
  • Neonatal meningitis consideration: the BBB is incompletely formed in neonates, allowing penicillin to cross into brain tissue

Volume of Distribution (Vd)

  • Vd provides an indication of how much of the total body drug is retained in plasma versus distributed into other compartments
  • Interpretations:
    • Low Vd: drug largely confined to plasma
    • High Vd: drug extensively distributed into extracellular tissues and/or fat stores
  • Formula: V_d = rac{D}{C} where D is the total amount of drug in the body and C is the plasma concentration
  • Example (plasma volume ~5 L):
    • Drug A: D = 100 mg, C = 1 mg/L → V_d = rac{100}{1} = 100 ext{ L}
    • Drug B: D = 100 mg, C = 20 mg/L → V_d = rac{100}{20} = 5 ext{ L}
    • Interpretation: Drug A has a high Vd (wide distribution); Drug B has a low Vd (confined largely to plasma)

Metabolism (Biotransformation)

  • Definition: chemical alteration of a drug in a living organism
  • Purpose: convert lipid-soluble, unionised drugs into water-soluble, ionised forms for excretion
  • If a drug is ionised on initial administration, it may not be well metabolised and may be excreted unchanged
  • Primary site: liver (with involvement of gut, kidneys, lungs, blood, skin, placenta, etc.)
  • Consequences of metabolism:
    • Active drug → inactive metabolites (most common)
    • Active drug → active metabolite (e.g., codeine → morphine), which can prolong action
    • Inactive drug → active metabolite (prodrug) (e.g., prednisone → prednisolone)
    • Active drug → toxic metabolite (e.g., paracetamol)
  • Prodrugs: advantages include increased bioavailability, longer duration, taste improvement, site-specific delivery
  • Phases of metabolism:
    • Phase I: chemical alteration (oxidation, reduction, hydrolysis) to increase water-solubility; metabolites may be active or inactive
    • Phase II: conjugation reactions; many Phase I metabolites are further conjugated to become inactive, polar, and water-soluble for excretion
  • Enzymes involved:
    • Microsomal enzymes (primarily in endoplasmic reticulum of hepatocytes) catalyze most Phase I reactions; cytochrome P450 enzymes; inducible
    • Non-microsomal enzymes (cytoplasm and mitochondria) catalyze most Phase II reactions; show genetic polymorphism; generally non-inducible
  • Factors modifying drug metabolism:
    • Age: neonates and elderly have reduced metabolic capacity; potential for increased toxicity
    • Diet: protein deficiency ↓ metabolism; protein-rich foods can ↑ metabolism of certain drugs; carbohydrate-rich foods may ↓ metabolism
    • Diseases: liver disease ↓ metabolism → longer action
    • Pharmacogenetics: genetic variations affect drug response (PK and PD)

Excretion (Elimination)

  • Definition: removal of drug and its metabolites from the body
  • Major route: kidney (urine)
  • Minor routes: lungs, bile, feces, sweat, saliva, milk
  • Excretion relates to the amount of drug removed per unit time
  • Clearance (PK concept related to excretion):
    • Defined as the volume of plasma from which the drug is completely removed per unit time
    • Formula (rate-based): Cl = rac{ ext{rate of elimination}}{Cp} where Cp is plasma concentration

Pharmacokinetics in Special Situations

  • Older age:
    • Slower gastric emptying delays delivery to small intestine
    • Reduced liver and kidney function affects metabolism and excretion
    • First-pass metabolism may be reduced, increasing oral bioavailability
    • Plasma protein levels may be lower → higher free drug fraction
    • Increased adipose stores → potential for drug accumulation in fat
    • Greater sensitivity to central effects (confusion, sedation, dizziness)
  • Drug compliance in the elderly:
    • Polypharmacy due to multiple conditions
    • Complex regimens increase error risk and interactions
    • Cognitive decline affects memory/regimen adherence
    • Sensory impairments (vision/hearing) hinder label comprehension and instructions
    • Physical limitations to access medications
  • Additional elderly factors:
    • Financial constraints and affordability of meds
    • Complex dosing schedules can be overwhelming
    • Lack of social support for reminders and assistance
    • Depression and mental health impact adherence
    • Health literacy barriers; understanding instructions
    • Side effects may provoke non-adherence
    • Healthcare system factors (refills, wait times, prescriptions)
  • Pregnancy and related considerations:
    • Fetal liver/kidney function are immature; fetus relies on mother for drug elimination
    • Pregnancy-associated nausea can affect oral dosing
    • Plasma volume rises, diluting plasma proteins and increasing free fraction
    • Cardiac output rises, increasing renal/hepatic blood flow and potentially accelerating elimination
    • Hepatic metabolism increases due to higher enzyme levels; faster clearance

Genetic Variability and Personalised Medicine

  • Genetic variability is a significant source of inter-individual PK variability; to be discussed in more detail
  • Personalised medicine aims to tailor therapy to individual patients based on genotype and phenotype
  • Pharmacogenetics: study of how genetic variation in DNA sequence affects genes encoding
    • Drug-metabolising enzymes
    • Drug transporters
    • Drug targets (receptors, ion channels, etc.)
  • Genetic polymorphisms can affect pharmacokinetic factors (absorption, distribution, metabolism, excretion) and pharmacodynamic factors (receptors, enzymes, ion channels, signaling)
  • Example: Codeine metabolism via CYP2D6
    • Codeine → morphine (active metabolite) via CYP2D6
    • Poor metabolisers → reduced analgesia; rapid metabolisers → higher risk of adverse effects
    • Population variation: ~6–10% Caucasians are poor metabolisers; ~0.5–1% Asians/Hispanics; ~1% Arabs; ~3% African Americans

Adverse Drug Reactions (ADRs)

  • ADRs are any noxious or unintended responses occurring at usual therapeutic doses
  • ADRs are common across ages but more likely in the very young and elderly; higher incidence in women
  • Categories:
    • Type A (predictable)
    • Type B (unpredictable)
    • Other subtypes: Type C (chronic use), Type D (delayed), Type E (withdrawal), Type F (unexpected failure of therapy)
  • Risk factors for ADRs:
    • Age, gender, concurrent diseases, drug class, polypharmacy, renal/hepatic impairment, genetics, prior reactions, dose/duration/frequency

Drug Interactions

  • Definition: situations where one drug interferes with pharmacokinetic or pharmacodynamic properties of another
  • Common causes: food, non-prescription medicines, herbal remedies, natural products
  • Not all interactions are harmful (e.g., salbutamol and steroids can have synergistic effects)
  • Types:
    • Pharmacokinetic interactions: affect ADME of another drug
    • Pharmacodynamic interactions: affect mechanism of action or signaling pathways
  • Pharmacokinetic interactions by process:
    • Absorption: e.g., dairy calcium complexes with tetracycline → insoluble complex; drugs slowing gastric motility can slow absorption
    • Distribution: competition for plasma protein-binding sites (e.g., warfarin and aspirin); displacement increases free drug
    • Metabolism: enzyme induction or inhibition; alters metabolism rate of affected drugs
    • Excretion: reduced renal function or renal blood flow can reduce excretion; specialized renal transporters can be inhibited
  • Specific examples of liver enzyme interactions:
    • Inhibitors (↓ metabolism of other drugs): SSRIs, Cimetidine, Erythromycin, Grapefruit/grapefruit juice
    • Inducers (↑ metabolism of other drugs): St John's Wort, Cruciferous vegetables (broccoli, Brussels sprouts), Garlic supplements, Goldenseal, Alcohol (chronic), Smoking
    • Acute alcohol can inhibit metabolism; chronic alcohol can induce metabolism
  • Note on contradictory list placement: inhibitors and inducers can vary by drug and context; the key concept is that some substances raise or lower other drugs’ levels via PK interactions
  • Examples of inhibitors/inducers and foods/herbs illustrate why monitoring and dose adjustments may be necessary in polypharmacy

Pharmacokinetics: Mathematical and Conceptual Notes

  • Volume of distribution: V_d = rac{D}{C}
    • D: total amount of drug in the body; C: plasma concentration
    • Example interpretation: higher Vd suggests wider distribution beyond plasma
  • Clearance (PK concept):
    • Cl = rac{ ext{Rate of elimination}}{C_p}
    • Clearance relates to how quickly a drug is removed from plasma, incorporating metabolism and excretion
  • Steady-state concepts:
    • Steady-state concentration is reached when input equals elimination over time
    • Time to steady state is approximately t{ss} \, \approx \ 4-5 \ times \ t{1/2}
    • For most drugs with regular dosing, steady state is achieved after 4–5 half-lives
    • Example: a drug with a 4-hour half-life reaches steady state after roughly 20 hours
    • For very long-half-life drugs (e.g., fluoxetine), steady state may take weeks
  • Practical steady-state development: after each dose, the amount in the body increases until a balance is reached; calculations can show how the body gradually accumulates toward steady state

Clinical Pharmacology and Therapeutics

  • Clinical pharmacology studies drug action in humans to guide safe and effective prescribing
  • Therapeutics is the application of pharmacology to treat diseases; aims to maximize benefits while minimizing harms
  • Good prescribing involves investigating and monitoring drug effects to devise dosing regimens within therapeutic ranges
  • Pharmacovigilance: monitoring the effects of medicines after approval; balancing benefits against risks
  • Interindividual variance in drug response arises from age, sex, ethnicity, body weight, environment, genetics, disease, pregnancy, and drug interactions
  • Personalised medicine uses genotyping and other data to tailor therapy to individuals or subgroups with similar phenotypes

Legends and Key Concepts (recap)

  • Absorption, distribution, metabolism, excretion (ADME) govern drug kinetics
  • Drug distribution is influenced by lipid solubility, ionisation, blood flow, and protein binding
  • PPB affects free drug availability, efficacy, and toxicity risk
  • The BBB protects the CNS; neonatal BBB is immature, affecting penetration of certain drugs
  • Metabolism transforms drugs to more water-soluble forms; Phase I (functionalization) and Phase II (conjugation) pathways
  • Enzyme induction and inhibition can drastically alter drug levels; contributors include foods, herbs, and other medications
  • Excretion via kidneys is primary; clearance integrates renal function and hepatic/metabolic contributions
  • Special populations require dose adjustments and monitoring (elderly, neonates/children, pregnancy)
  • Pharmacogenetics explains why patients may respond differently due to genetic variation in enzymes, transporters, and targets
  • ADRs are a major clinical consideration; risk factors include age, polypharmacy, and organ function
  • Missed doses and dosing strategies impact achieving and maintaining steady-state concentrations