Pharmacology Fundamentals

What is Pharmacology?

• Pharmacology is the science of drugs, their origins, compositions, pharmacokinetic use, toxicology, etc.
• Distinction between a "drug" and a "medicine":
  • Drug: a man-made or natural endogenous molecule with a biochemical or physiological effect on the cell, tissue, or organism.
  • Medicine: prevents, alleviates, or cures symptoms or diseases, carefully produced, tested, approved, and regulated.

Sources of Drugs

• Examples of drugs derived from natural sources:
  • Willow tree (Salicylates)
  • Belladonna (atropine)
  • Sweet wormwood (antimalarial drug)
• Examples of drugs derived from synthetic sources:
  • Aspirin

Drug Nomenclature

• Names of drugs can be categorized into three types:
  • Chemical name
  • Generic name (e.g., statin, Prazole, Oxetine, Sartan)
  • Brand name

Drug Development Process

• Involves scientists, clinicians, pharmaceutical companies, and regulators
• Key milestones:
  • 1920s: Banting and insulin for treatment
  • 1928: Alexander discovers penicillin in mould

Key Pharmacological Concepts

• Therapeutic index: the ratio of the blood concentration at which a drug causes death or toxicity to the amount that causes a therapeutic effect
• Drug absorption:
  • Process by which a drug moves from its site of administration to the systemic circulation
  • Factors affecting oral absorption: physicochemical properties, biological factors, and transporters

Drug Distribution

• Reversible passage of drugs between tissues, organs, and compartments
• Major body compartments: intravascular fluid, interstitial fluid, intracellular fluid, and body fat
• Factors influencing drug distribution:
  • Solubility
  • Local pH
  • Blood flow
  • Tissue binding
  • Plasma protein binding
• Important plasma proteins for drug binding:
  • Alpha1 acid glycoprotein
  • Human serum albumin (HSA)

Drug Metabolism

• Chemical change of a drug into one or more products in the body
• Main sites involved: liver and gut wall (first-pass metabolism)
• Phase 1 metabolism: lipophilic drugs are metabolized to become more hydrophilic
  • Examples: oxidation, hydrolysis
• Phase 2 metabolism: hydrophilic drugs are converted into more hydrophilic products for renal excretion
  • Examples: glucuronidation
• Outcomes of drug metabolism:
  • Increase molecular size to facilitate renal excretion
  • Decrease drug elimination half-life
  • Alter pharmacological activity of the parent drug
  • Terminate action of the drug

CYP450 Enzymes

• Important family of drug-metabolizing enzymes
• Found on the endoplasmic reticulum of hepatocytes
• Use NADPH and O2 to metabolize xenobiotics/drugs
• Two important CYP450 members:
  • CYP3A4: most important enzyme with broad substrate specificity
  • CYP2D6: most polymorphic enzyme

Drug-Drug Interactions

• Caused by CYP450-mediated interactions
• Examples:
  • Ethanol and paracetamol
  • CYP induction (phenobarbital)
  • CYP inhibition (ritonavir and cobicistat)

Drug Excretion

• Irreversible physical removal of a drug and its metabolites from the body
• Factors affecting drug excretion:
  • Urine pH
  • Renal blood flow
  • Drug concentration in plasma
  • Impaired renal function
  • Plasma protein binding
  • Molecular size and weight
  • Transporters (SLC transporters)
• Routes of drug excretion:
  • Renal excretion (kidneys)
  • Faeces (bile)
  • Breast milk
• Fu: the fraction of drug unbound that is unbound in plasma

Renal Drug Excretion

• Three processes involved:
  1. Glomerular filtration
  2. Active tubular secretion
  3. Passive reabsorption
• Clinical application: importance of urine pH and transporters in renal excretion

Enterohepatic Recirculation

• The metabolizing and reabsorption of a drug back into systemic circulation via hepatic pathways
• Example: morphine

Individual Variations in Drug Response

• Affected by intrinsic and extrinsic factors
• Intrinsic factors: age, genetics, sex, disease status
• Extrinsic factors: concomitant medication, diet, and exposure to chemicals and other environmental causes

CYP Single Nucleotide Polymorphism (SNP)

• Relationship between CYP SNP, phenotype, and metabolism of a pharmacologically active parent drug or a prodrug
• Four types of phenotypes represent metabolizers in the population

Drug Clearance

• How efficiently a drug is eliminated from the volume of plasma
• Relationship between fe and hepatically cleared drugs and renally cleared drugs
• Simple approach to determine total body clearance in non-compartmental analysis (NCA)

Drug Bioavailability

• The fraction of the administered dose that reaches systemic circulation
• To calculate the bioavailability of orally administered drugs, use the formula: F = AUCoral / AUCiv

Test your knowledge of pharmacology basics, including the origin of the term, differences between drugs and medicines, and key concepts in drug development.