5. principle drug

• Pharmacology is the study of drugs, their uses, and how they affect organisms
• Pharmacokinetics describes what the body does to a drug
• Pharmacodynamics describes what the drug does to the body
• Pharmacokinetics (ADME) determines:

  • The speed of onset of drug action
  • The intensity of the drug effect
  • The duration of drug action
• ADME stands for:

  • Absorption: The drug absorption from the site of administration which allows the entry of the therapeutic agent into the plasma
  • Distribution: The drug leaves the bloodstream and distributes into the interstitial and intracellular fluids
  • Metabolism: Biotransformation of the drug into metabolites by the liver or other tissues
  • Elimination: The drug and its metabolites are eliminated into urine, bile, or feces
• Routes of Drug Administration:

  1. Enteral: Oral, Sublingual

  2. Parental: Intravenous (IV), Intramuscular (IM), Subcutaneous (SC)

  3. Other Routes: Inhalation, Intrathecal, Topical, Transdermal, Rectal
• Enteral Route:

  • Oral administration
  • Advantages: Easy self-administration, low risk of systemic infection, easier to manage toxicity
  • Disadvantages: Inactivation of drugs due to first-pass effect or stomach acidity
• Enteral Route cont...

  • Oral administration can be:
  • Enteric coated: To protect the stomach from the drug or to protect the drug from stomach acidity
  • Extended release: To control how fast the drug is released from the pill into the body
• Parenteral Route:

  • Direct administration of the drug across body barriers into the systemic circulation
  • Used for drugs with poor GI absorption, drugs unstable in the GI, unconscious patients, rapid onset of action, and high bioavailability
• Parenteral Route cont...

  • Advantages: No first-pass metabolism
  • Disadvantages: Risk of infection, can be irreversible
• Other Routes:

  • Inhalation: Oral or nasal, rapid delivery across the large surface area of mucous membrane
  • Intrathecal: Direct injection into the cerebrospinal fluid, rapid delivery to avoid the blood-brain barrier
  • Transdermal: Sustained delivery of drugs
  • Rectal: Avoids first-pass metabolism, rapid delivery used when oral is not possible
• Drug Absorption:

  • Absorption is the transfer of a drug from the site of administration to the bloodstream via several mechanisms
  • The rate and efficiency of absorption depend on the environment, chemical characteristics of the drug, and route of administration
• What is Bioavailability:

  • The fraction of administered drug that reaches the systemic circulation
  • Example: If 100 mg of a drug was administered orally and 70 mg were absorbed unchanged, the bioavailability is 70%
• Factors that influence oral bioavailability:

  • First-pass hepatic metabolism
  • Nature of the drug formulation
  • Solubility of drug formulation
  • Solubility of the drug
  • Chemical instability
  • Decomposition in acidic gastric juices
  • Decomposition in hydrolytic gut enzymes
  • Degradation by gut microorganisms
  • Food in the gut
  • Metabolism by gut wall enzymes
• First Pass Effect:

  • Drugs absorbed via the GIT are circulated to the liver first via the hepatic portal vein
  • Liver acts as a filter, only some part of the drug is circulated back systemically
  • The combination process is termed the First Pass effect
• Mechanisms of drug absorption from the GI tract:

  1. Passive diffusion

  2. Facilitated diffusion

  3. Active transport

  4. Endocytosis and exocytosis
• Passive Transport:

  • Does not require energy
  • Can be saturated and inhibited by compounds that compete for the carrier
• Active Transport:

  • Involves specific carrier proteins
  • Requires energy
  • Moves drugs against the concentration gradient (from low to high concentration regions)
  • Selective, saturable, and can be inhibited by co-transported substances
• Endocytosis:

  • Cellular process where substances are brought into the cell by engulfing them with the cell membrane, forming a vesicle
• Exocytosis:

  • The reverse process of endocytosis, involving the regular secretion of molecules by releasing membrane proteins and lipids to the cell's surface and expelling substances to the cell's exterior
• Factors influencing absorption:

  1. pH

  2. Blood flow

  3. Total surface area

  4. Contact time

  5. Expression of p-glycoprotein
• Factors influencing absorption cont...

  1. pH:

  • Most drugs are weak acids or weak bases
  • Drugs pass through membranes easier when uncharged
• Factors influencing absorption cont...

  2. Blood flow to the absorption site:

  • Blood flow is much greater in the intestines than the stomach, leading to greater absorption in the intestines
• Factors influencing absorption cont...

  3. Total surface area available for absorption:

  • Intestines have a larger surface area for absorption
• Factors influencing absorption cont...

  4. Contact time at the absorption surface:

  • Absorption is affected by changes in gastric motility
• Factors influencing absorption cont...

  5. Expression of p-glycoprotein (protein of cell membrane):

  • Drug transporter with high expression reduces absorption
  • Expressed in kidney, placenta, intestines, and brain capillaries
• Drug Distribution:

  • The process by which a drug leaves the bloodstream and enters the interstitial and cells
  • For IV drugs, distribution occurs immediately after administration
• Plasma Half-Life (t ½) of drugs:

  • Length of time needed to decrease drug plasma concentration by half
  • Determines frequency and dosages
• Drug Metabolism:

  • Involves hepatic metabolism, elimination in bile, and urine
  • Metabolism leads to products with increased polarity for drug elimination
• Metabolism Kinetics:

  1. First-order kinetics: rate of drug metabolism is directly proportional to drug concentration

  2. Zero-order kinetics: rate of metabolism is constant and does not depend on drug concentration
• Reactions of drug metabolism:

  • Kidneys cannot efficiently eliminate lipophilic drugs as they get reabsorbed in distal convoluted tubules
  • Lipid-soluble agents must be metabolized into more polar substances in the liver
• Drug metabolism in Liver:

  • Phase I reactions involve oxidation, reduction, or hydrolysis of the parent drug
  • Phase II reactions involve conjugation by coupling the drug or its metabolites to another molecule
• Phase I Metabolism:

  • Conversion of lipophilic molecules into more polar molecules by adding a polar group
  • Involves P450 enzymes
• P450 enzymes:

  • A superfamily of enzymes that oxidize various compounds and are important for drug clearance
• P450 enzymes:

  • Inducers increase metabolism
  • Inhibitors cause drug interactions
• Phase II metabolism:

  • Involves conjugation reactions to make metabolites water-soluble
• Drug Excretion:

  • Main route for drug removal is through the kidney into the urine
  • Drugs need to be polar enough for efficient excretion
• Renal elimination:

  • Involves glomerular filtration, proximal tubular secretion, and distal tubular reabsorption
• Clearance by other routes:

  • Liver, intestine, bile, lungs, breast milk, sweat, tears, saliva, hair, and skin
• Alterations in t ½ of drugs:

  • Diminished renal or hepatic flow increases t ½
  • Decreased ability to extract drug from plasma increases t ½
  • Decreased metabolism increases t ½
  • Increased hepatic blood flow reduces t ½
  • Decreased protein binding reduces t ½
  • Increased metabolism reduces t ½