Pharmacokinetics ADME

Glomerular Filtration

• Molecular size restricts glomerular filtration
• Lipid solubility does not affect glomerular filtration
• Highly protein-bound drugs are negligibly filtered
• Only unbound drugs are filtered
• Reduced glomerular filtration occurs with age and kidney disease, diminishing drug excretion

Active Secretion

• Proximal tubule actively secretes free and bound drugs
• Two active secretion pumps exist
• Highly cleared drugs have a clearance rate equivalent to renal blood flow
• These pumps are responsible for secreting:
  • Bases, e.g., Pancuronium
  • Acids, e.g., Penicillin, Thiazide diuretics

Drug Excretion Based on Lipid Solubility

• Water-soluble drugs are excreted in urine
• Lipid-soluble drugs re-enter the bloodstream

Factors Influencing Drug Metabolism and Therapeutic Window

• Pharmacokinetic factors: Starvation, Fever, Alcohol intake, Cigarette Smoking, Cardiovascular function, Liver function, Renal function, Gastrointestinal function
• Genetic Factors: Influence drug metabolism and response
• Other factors: Age, Sex, Dietary Factors, Herbals, Drugs

Pharmacokinetics (ADME) - Overview

• ADME stands for Absorption, Distribution, Metabolism, Excretion
• Understanding pharmacokinetics is crucial for drug prescribers

Drug Absorption

• Routes of administration:
  • Oral: Tablets, capsules (most common)
  • Rectal: Suppositories (Diazepam), rectal foams (steroids)
  • Sublingual: Tablets, sprays (Glyceryl Trinitrate)
• Gastric emptying: Determines drug absorption; faster emptying leads to quicker absorption
• Intestinal surface area: Small intestine is the primary site of absorption due to its larger surface area
• First-pass metabolism: Drugs metabolized in the liver before reaching systemic circulation
• Bioavailability: Fraction of a drug dose reaching systemic circulation following oral administration. Factors influencing bioavailability include:
  • Drug absorption
  • First-pass metabolism

Drug Distribution

• Protein binding: Drugs bind to proteins like albumin and α1-acid glycoprotein in the bloodstream, influencing their distribution
• Blood flow: Blood flow to different tissues influences drug distribution
• Body compartments: Drugs can accumulate in specific compartments, including:
  • Blood-brain barrier
  • Placental barrier
• Cell membrane: The cell membrane controls drug movement between the extracellular and intracellular fluids

Drug Metabolism

• Lipid solubility: Lipid-soluble drugs are more readily metabolized
• Phase I metabolism: Primarily involves oxidation, reduction, or hydrolysis, changing the drug's structure and making it more water-soluble
• Phase II metabolism: Conjugation reactions, adding a polar group to the drug molecule to improve its water solubility and excretion
• Liver enzymes: Primarily Cytochrome P450 enzymes, involved in drug metabolism and can be inhibited or induced by various substances, resulting in drug interactions
• Genetic polymorphism: Individual variations in genes encoding drug-metabolizing enzymes, leading to differences in drug metabolism and response
• Prodrugs: Inactive forms of drugs that become active after metabolism

Drug Excretion

• The primary route of drug excretion is through urine
• Metabolism increases drug water solubility, facilitating renal excretion
• Renal excretion is influenced by glomerular filtration and active secretion in the proximal tubule
• Factors like age, renal function, and drug characteristics can affect excretion rates

Drug Interactions

• Inhibitors block the activity of drug-metabolizing enzymes, increasing a drug's concentration and potential for adverse effects (e.g., Erythromycin, Ketoconazole).
• Substrates are drugs that are metabolized by a specific enzyme (e.g., Midazolam, Cyclosporin).
• Inducers enhance the activity of drug-metabolizing enzymes, decreasing a drug's concentration and effectiveness (e.g., Rifampicin, Carbamazepine)

Genetic Polymorphism In Drug Metabolism

• Poor metabolizers lack certain drug-metabolizing enzymes (e.g., CYP2D6), leading to higher drug concentrations and potential toxicity
• Extensive metabolizers possess normal levels of these enzymes.
• This impacts various drugs including cardiovascular, psychiatric, and analgesic medications

Prodrugs

• Prodrugs are inactive drug forms converted to their active forms by metabolism.
• Ramipril is an example, metabolized to Ramiprilat, an active antihypertensive drug. This conversion is mediated by the enzyme, Carboxyesterase 1, in human liver.

This quiz explores key concepts in pharmacokinetics, focusing on glomerular filtration, active secretion, and factors influencing drug metabolism. Understand how molecular size, lipid solubility, and various physiological factors affect drug clearance and therapeutic outcomes.