Part1

• Pharmacodynamic processes

  The actions of the drug on the body
• Pharmacokinetic processes

  The actions of the body on the drug
• Pharmacokinetics

  1. Absorption

  2. Distribution

  3. Metabolism

  4. Elimination

  
• Pharmacokinetic parameters


  • Clinicians can design optimal drug regimens, including the route of administration, the dose, the frequency, and the duration of treatment

  
• Routes of drug administration

  • Enteral
  • Parenteral
  • Topical
  • Others
• Enteral administration

  Administering a drug by mouth, including swallowing, sublingual, or buccal
• Enteric-coated preparations

  • Protect the drug from stomach acid, delivering it to the less acidic intestine
  • Useful for acid labile drugs or drugs irritating to the stomach
• Extended-release preparations

  • Have special coatings or ingredients that control drug release, allowing for slower absorption and prolonged duration of action
  • Can be dosed less frequently and may improve patient compliance
  • Maintain concentrations within the therapeutic range over a longer duration
• Sublingual/buccal routes

  • Involve placement of drug under the tongue or between the cheek and gum
  • Advantages include ease of administration, rapid absorption, bypass of the GI environment, and avoidance of first-pass metabolism
• Parenteral administration

  • Introduces drugs directly into the body by injection
  • Used for drugs poorly absorbed from the GI tract or unstable in the GI tract, when rapid onset of action is needed, or when patient cannot take oral medications
• Major parenteral routes


  • Intravascular (intravenous or intra-arterial)
  • Intramuscular
  • Subcutaneous
• Depot preparations


  • Consist of a suspension of drug in a nonaqueous vehicle
  • As the vehicle diffuses out, drug precipitates at the site of injection and dissolves slowly, providing sustained dose over an extended interval
• Subcutaneous injection


  Provides absorption via simple diffusion, slower than IV, minimizes risks of hemolysis or thrombosis, may provide constant, slow, and sustained effects

  
• Intradermal injection


  • Involves injection into the dermis, the more vascular layer of skin under the epidermis
  • Used for diagnostic determination and desensitization
• Other routes of administration

  • Oral inhalation and nasal preparations
  • Intrathecal/intraventricular
  • Topical
  • Transdermal
  • Rectal
• Absorption


  The transfer of a drug from the site of administration to the bloodstream

  
• Mechanisms of drug absorption from the GI tract

  • Passive diffusion
  • Facilitated diffusion
  • Active transport
  • Endocytosis and exocytosis
• Passive diffusion


  Drug moves from an area of high concentration to one of lower concentration, does not involve a carrier, is not saturable, and shows low structural specificity

  
• Facilitated diffusion


  Involves specialized transmembrane carrier proteins that facilitate the passage of drugs or endogenous molecules, does not require energy, can be saturated, and may be inhibited by competing compounds

  
• Active transport


  Energy dependent, driven by ATP hydrolysis, can move drugs against a concentration gradient, is selective and may be competitively inhibited

  
• Endocytosis and exocytosis


  Used to transport exceptionally large drugs across the cell membrane, endocytosis involves engulfment and internalization, exocytosis is the reverse process of secretion

  
• Factors influencing drug absorption

  • Effect of pH
  • Blood flow to absorption site
  • Surface area available
  • Contact time at absorption surface
  • Expression of P-glycoprotein

  
• 1. glycoprotein


  A transmembrane transporter protein that pumps drugs out of cells, reducing drug absorption in areas of high expression

  
• Bioavailability is the fraction of an administered dose that reaches the systemic circulation

  
• Intestine


  • Surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient
• Contact time at the absorption surface

  If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug

  
• 1. glycoprotein


  A trans-membrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. It "pumps" drugs out of the cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption. It is also associated with multidrug resistance

  
• Bioavailability


  The rate and extent to which an administered drug reaches the systemic circulation

  
• If 100 mg of a drug is administered orally and 70mg is absorbed unchanged, the bioavailability is 0.7 or 70%
• Determination of bioavailability


  Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured

  
• Factors that influence bioavailability

  • First-pass metabolism, solubility of the drug, chemical instability, nature of the drug formulation
• First-pass hepatic metabolism


  When a drug is absorbed from the Gl tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased

  
• Solubility of the drug

  Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions

  
• Chemical instability


  Some drugs, such as penicillin G, are unstable in the pH of gastric contents. Others, such as insulin, are destroyed in the Gl tract by degradative enzymes
• Nature of the drug formulation


  Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption

  
• Drug distribution


  The process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues

  
• Factors affecting drug distribution

  • Cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug

  
• Blood-brain barrier


  The closely juxtaposed endothelial cells in the brain capillaries form tight junctions that constitute the blood-brain barrier, which prevents ionized or polar drugs from entering the brain

  
• Factors affecting drug distribution

  • Blood flow, capillary permeability, binding of drugs to plasma proteins and tissues, lipophilicity

  
• Volume of distribution (Vd)

  The fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0)