Pharmacology

• Pharmacology


  The study of the actions, mechanisms, uses, and adverse effects of drugs
• Drug


  A natural or synthetic substance that alters the physiological state of a living organism
• Types of drugs


  • Medicinal drugs (used for prevention, treatment, and diagnosis of disease)
  • Non-medicinal drugs (used for recreational purposes)
• Although drugs may have a selective action, there is always a risk of adverse effects associated with the use of any drug
• Brand name


  The name given by the company that makes the drug, usually easy to say for sales and marketing purposes
• Generic name


  The name of the active ingredient
• Properties used to classify drugs

  • Pharmacotherapeutic actions (desired effect)
  • Pharmacological actions (mechanism of action)
  • Molecular actions (mechanism of action at the molecular level)
  • Chemical nature
• Pharmacokinetics


  The study of the time course of drug absorption, distribution, metabolism, and excretion
• Pharmacodynamics


  The study of the biochemical and physiological effects of a drug and their mechanism of action at the organ, subcellular, and macrocellular levels
• Pharmacokinetics is the body's action on the drug, while pharmacodynamics is the drug's action on the body
• Pharmacokinetic example


  • Paracetamol: rapidly absorbed orally, 25% bound to plasma protein, widely and uniformly distributed, extensively metabolized in the liver, excreted in urine
• Pharmacodynamic example


  • Loperamide: acts on opioid receptors and the myenteric plexus of the large intestine, decreases smooth muscle tone and delays the passage of intestinal content
• Most drugs produce their effects by targeting specific cellular macromolecules, often proteins, such as receptors, enzymes, and transporter molecules
• Some drugs work by means of their physical-chemical properties and have a non-specific mechanism of action, such as chelating agents that bind to metals
• Routes of drug administration

  • Oral
  • Intravenous
  • Subcutaneous
  • Intramuscular
  • Transdermal
  • Rectal
  • Inhalation
  • Sublingual
• Oral absorption


  Variable, affected by many factors, limited absorption of some drugs, food may affect absorption, patient compliance is necessary, drugs may be metabolized before systemic absorption
• Intravenous absorption


  Immediate effects, ideal for large volumes, suitable for irritating substances and complex mixtures, valuable in emergency situations, dosage titration is permissible, ideal for high molecular weight proteins and peptides
• Subcutaneous absorption


  Depends on drug diluent, aqueous solution is prompt, depot preparations are slow and sustained, suitable for slow release drugs, unsuitable for drugs administered in large volumes
• Intramuscular absorption


  Depends on drug diluent, aqueous solution is prompt, depot preparations are slow and sustained, suitable for moderate drug volumes, suitable for oily vehicles and irritating substances, preferable to intravenous if patient must self-administer
• Transdermal absorption


  Slow and sustained, bypasses first-pass effect, convenient and painless, ideal for lipophilic drugs with poor oral bioavailability, limited to drugs that can be taken in small daily doses
• Rectal absorption


  Erratic and variable, partially bypasses first-pass effect, bypasses destruction by stomach acid, ideal if drug causes vomiting, not a well-accepted route
• Inhalation absorption


  Systemic absorption not always desirable, rapid absorption and immediate effects, ideal for gases, effective for respiratory problems, lower doses compared to oral or parenteral, fewer systemic side effects
• Sublingual absorption


  Depends on the drug, rapid direct systemic absorption, bypasses first-pass effect and destruction by stomach acid, maintains drug stability, may cause immediate pharmacological effects, limited to certain types of drugs and small doses
• Absorption


  Movement of drug from its site of administration to the systemic circulation
• Factors affecting absorption


  Lipid solubility, molecular size, pH, bioavailability
• Mechanisms of absorption


  Passive diffusion, facilitated diffusion, active transport, endocytosis
• Facilitated diffusion


  1. Carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells

  2. Moving from an area of high concentration to an area of low concentration

  3. Does not require energy
• Active transport


  • Few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using specific carrier proteins
  • Energy dependent, driven by the hydrolysis of adenosine triphosphate
  • Capable of moving drugs against a concentration gradient from a region of low drug concentration to one of higher drug concentration
  • Saturable
• Endocytosis


  • Type of absorption used to transport drugs of exceptionally large size across the cell membrane
  • Involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle
• Exocytosis


  • Reverse of endocytosis
  • Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation
  • Certain neurotransmitters are stored in intracellular vesicles in the nerve terminal and released by exocytosis
• Distribution


  • Once drugs have reached the circulation, they reversibly leave the bloodstream and enter the interstitium, extracellular fluid and the tissues
  • Depends on cardiac output, local blood flow, capillary permeability, tissue volume, degree of binding to plasma and tissue proteins, and relative lipophilicity of the drug
• Apparent volume of distribution (Vd)

  • Calculated pharmacokinetic space in which a drug is distributed
  • Equals amount of drug in the body over initial apparent plasma concentration
• Metabolism


  1. Leads to production of products with increased polarity which allows the drug to be eliminated

  2. Liver is the major site, but other sites include kidney, lung, and gastrointestinal tract

  3. Diseases of these organs may affect a drug's pharmacokinetics
• First pass metabolism


  Orally administered drugs may be extensively metabolized in the small intestine and liver before reaching the systemic circulation
• Phase 1 metabolism


  1. Convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group

  2. Involve reduction, oxidation or hydrolysis

  3. May increase, decrease or have no effect on pharmacologic activity
• Phase 2 metabolism


  1. Conjugation reactions with endogenous substrates like glucuronic acid, sulfuric acid, acetic acid or amino acids

  2. Results in polar, usually more water soluble compounds that are often therapeutically inactive
• Excretion


  • Predominantly occurs via the kidneys into urine or by the gastrointestinal tract into bile and feces
  • Volatile drugs are predominantly exhaled by the lungs
  • To a lesser extent, drugs may leave the body through breast milk and sweat
• Renal excretion


  Glomerular filtration, tubular reabsorption (passive and active), and tubular secretion determine the extent of drug excretion
• Gastrointestinal excretion


  Some drug conjugates are excreted into the bile and subsequently released into the intestines where they are hydrolyzed back to the parent compound and reabsorbed (enterohepatic circulation)
• Drug targets


  • Enzymes - drugs may act as false substrates or inhibit enzyme activity
  • Receptors - drugs may act as agonists or antagonists