Pharmacology Course: Pharmacokinetics and Bioavailability

Pharmacokinetics

• Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation
• Factors that determine bioavailability:
  • Biological factors: GIT degradation, food and other drugs, absorption, first-pass metabolism, and entero-hepatic circulation
  • Pharmaceutical factors: particle size, disintegration agents, and type of excipient

Distribution

• Volume of distribution (Vd) is the apparent volume in which a drug is distributed in the body
• Calculated by: Vd = Volume of distribution / Cp (plasma concentration per liter at the time of plasma-tissue equilibrium after i.v. injection)
• Distribution involves:
  • Blood-brain and CSF barriers: water-soluble drugs cannot filter into CSF or brain; crossing occurs by diffusion or carrier-mediated transport
  • Placental barrier
  • Plasma protein binding

Metabolism (Biotransformation)

• Metabolic processes convert lipid-soluble drugs into water-soluble products for elimination
• Two types of chemical reactions:
  1. Phase I reaction (non-synthetic): oxidation, reduction, and hydrolysis by microsomal enzymes
  2. Phase II reaction (synthetic): conjugation involving addition of an endogenous water-soluble group by transferases enzymes (e.g., glucuronidation, acetylation, methylation)

Metabolism (Biotransformation) - First Pass Effect

• Pre-systemic elimination that occurs after oral administration only
• Includes:
  • Intestinal first pass effect (intestinal lumen and intestinal wall)
  • Hepatic first pass effect (portal circulation and microsomal enzymes)
• Factors affecting the first pass effect:
  • Hepatic diseases (decrease first pass effect)
  • Hepatic enzyme induction (increase first pass effect)
  • Hepatic enzyme inhibition (decrease first pass effect)
  • Saturation of metabolizing enzymes (decrease first pass effect)

Enzyme Induction and Inhibition

• Enzyme induction: microsomal metabolizing enzymes increase, reducing drug efficacy and plasma half-life
• Examples of enzyme inducers and affected drugs:
  • Cigarettes (benzpyrene): benzodiazepines, paracetamol, propoxyphine, and theophyline
  • Barbiturates (phenobarbitone): barbiturates, phenytoin, warfarin, and doxycycline
  • ...
• Enzyme inhibition: microsomal metabolizing enzymes decrease, increasing drug efficacy and plasma half-life
• Examples of enzyme inhibitors and affected drugs:
  • Cimetidine: diazepam, phenytoin, antidepressants, and theophylline
  • Erythromycin: theophylline, warfarin, and cyclosporine
  • ...

Factors Affecting Metabolism

• Age and sex
• Diseases
• Drugs
• Genetic factors

Metabolic Products

• Usually biologically active → biologically inactive
• Or active drug → active metabolite (e.g., diazepam → oxazepam and desmethyldiazepam)
• Pro-drug (inactive) → active metabolite (e.g., prednisone → prednisolone)
• Metabolic product can be toxic (e.g., sulphonamides → acetyl derivative)

Elimination

• Routes of excretion:
  • Renal
  • Liver (bile excretion)
  • Lungs (volatile gases, gaseous anesthetics, and few ethanol)
  • Gastrointestinal tract (GIT)
  • Breast milk
  • Miscellaneous (sweat, saliva, hair, nails, skin)
• Clearance:
  • Total clearance = Cl renal + Cl liver + Cl others
  • Rate of clearance
  • Kinetics of clearance (first-order kinetics and zero-order kinetics)

Elimination - Half-Life (t ½)

• Time taken for circulatory plasma concentration to fall by 50%
• Factors affecting t ½:
  • Rate of clearance
  • Distribution and storage
  • Plasma protein binding
• Expectation of t ½:
  • Not indicative of duration of action and dosage schedule in certain cases (e.g., active metabolites, "hit and run" drugs, dose-dependent pharmacokinetics, and pathological conditions)

Pharmacokinetic Models

• Multi-compartment distribution: two-compartment model with an early distribution phase followed by a slower elimination phase
• Single-compartment distribution: some drugs behave as if they are distributed to only one compartment

Steady-State Level (SS)

• When intake of a drug is equal to its elimination, reached after 5 half-lives (t ½)
• Two important points:
  1. Time to reach SS level is a function of t ½ (5 half-lives) irrespective of dose or dose interval
  2. SS level reached is a function of dose and dose interval, not of t ½

Dosage Regimen

• Variables to consider:
  • Amount of single dose
  • Route of administration
  • Dose interval
  • Total duration of therapy
• Single-dose treatment (e.g., hypnotics, analgesics, and purgatives) and multiple dosing
• Variants of dosage schedule:
  • Drugs with short plasma t ½ (e.g., dopamine)

Pharmacodynamics

• Describes the actions of a drug on the body
• Most drugs exert effects by interacting with specialized target macromolecules called receptors, which are present on or in the cell

Fundamentals of Drug Action

• Activation: A drug molecule binds to the target site, stimulating a process or selectively accelerating it (e.g., caffeine causes CNS stimulation and increased alertness)
• Inhibition: A drug molecule binds to the target site, inhibiting a process or selectively deaccelerating it (e.g., aspirin inhibits cyclooxygenase, thereby inhibiting the formation of prostaglandins)
• Complexation: A drug molecule binds to the target site, making a complex, thereby making it inactive by sequestration (e.g., deferoxamine chelates iron)
• Neutralization: A drug molecule binds to the target site, neutralizing the action of the existing molecule directly through a chemical reaction or physical interaction (e.g., antacids, polyvalent anti-snake venom)

Signal Transduction

• Drugs act as signals, and receptors act as signal detectors
• An agonist binds to a site on a receptor protein, activating it to initiate a series of reactions that ultimately result in a specific intracellular response
• "Second messenger" or effector molecules are part of the cascade of events that translates agonist binding into a cellular response

Major Receptor Families

• Transmembrane Ligand-Gated Ion Channels: The channel is usually closed until the receptor is activated by an agonist, which opens the channel for a few milliseconds (e.g., cholinergic nicotinic receptor)
• Transmembrane G Protein-Coupled Receptors: The extracellular portion of this receptor contains the ligand-binding site, and the intracellular portion interacts with a G protein when activated (e.g., α and β adrenoceptors)
• Enzyme-Linked Receptors: This family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity (e.g., growth factors and insulin receptors possess tyrosine kinase activity)

Response of Drug-Receptor Interaction

• Agonists: Drugs that bind to receptors and produce a response (e.g., noradrenaline, acetylcholine)
• Antagonists: Drugs that have affinity to receptors without intrinsic activity (e.g., antiadrenergic)
• Partial Agonists: Drugs that have affinity but very low intrinsic activity
• Inverse Agonists: Drugs that produce actions specifically opposite to those of agonists (e.g., B-carbolines)

Combined Use of Drugs

• Synergism: The combined effect of two drugs is greater than the sum of their individual effects (e.g., additive, potentiation)
• Antagonism: The combined effect of two drugs is less than the sum of their individual effects (e.g., naloxone and opioid drugs)

Therapeutic Index (Safety Margin)

• The range of effective doses and the range of toxic doses are determined in humans
• The therapeutic index is a measure of the safety margin of a drug, which is the ratio of the toxic dose to the effective dose

Mechanism of Drug Action

• On Cell Membrane: Action of receptors, enzymes, and pumps, as well as physico-chemical interactions
• On Intracellular Constituents: Action on cytosolic or nuclear receptors, enzymes, DNA or RNA, and transport carrier molecules
• Outside the Cell: Chemical interaction, physical mechanisms, and antimicrobial action

Structure-Activity and Receptor Classes

• Structure-Activity Relationship: The same receptor type may mediate two effects, and a competitive antagonist will inhibit both responses of the agonist
• Stereoselectivity: Drug molecules have more than one 3-dimensional configuration, with different biological activity for each
• Receptor Classes: There are multiple receptor subtypes for each endogenous ligand (e.g., Ach, NA, H, 5-HT)

Quantitative Variation in Drug Response

• Up and Down Regulation of Receptors: The number of receptors can increase or decrease in response to changes in receptor activity
• Desensitization and Tachyphylaxis: A decrease in responsiveness to a drug due to changes in receptors or the loss of receptors
• Tolerance: A gradual decrease in responsiveness to a drug over time, requiring higher doses to achieve the same effect
• Drug Resistance: A decrease in responsiveness to a drug due to genetic changes or other factors

Dose-Response Relationships

• Graded Dose-Response Relations: The pharmacologic effect of a drug increases gradually as the concentration of the drug increases
• Potency: A measure of the amount of drug necessary to produce an effect, determined by the EC50 (the concentration of drug producing 50% of the maximum effect)
• Efficacy: The magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug-receptor complexes formed and the intrinsic activity of the drug

This quiz covers the concepts of pharmacokinetics and bioavailability, including the factors that determine bioavailability of a drug in the human body.