M4 PCOL: Pharmacodynamics

• Pharmacodynamics


  what the drug does to the body

  studies the drug effect and drug action
• drugs


  used to cure, treat, mitigate, diagnose, and prevent a disease

  substance that is capable of modifying the physiology of the body to maintain homeostasis

  a substance that has a physiological effect when ingested or otherwise introduced into the body
• Type of Drugs


  Functional modifiers

  Replenishers

  Diagnostic

  Chemotherapeutic
• Functional modifiers


  alters the normal physiology or processes in the human body

  most common

  examples: alteration of anxiety (buspirone, diazepam), alteration of pain (morphine, paracetamol)
• Replenishers


  supplement the existing endogenous compound that are deficient or lacking in concentration

  examples: IDDM (insulin), diarrhea (ORS), folate deficiency - megaloblastic anemia (folic acid)
• Diagnostics


  used to determine the presence or absence of diseases

  examples: myasthenia gravis (tensilon test: edrophonium), GIT disorders (barium sulfate), asthma (methacholine)
• Chemotherapeutics


  kill or inhibit the growth of cancer cells (antineoplastics)

  kill or inhbit the growth of bacteria (antimicrobials)
• Receptors

  protein molecules which bind to a chemical signalling molecule

  undergoes a conformational change which activates signaling pathway to bring a cellular response
• Types of Receptor

  Ionotropic receptors / Ligand gated ion channels

  G protein coupled receptors / Metabotropic receptors

  Enzyme linked receptors / Tyrosine kinase receptors

  Nuclear receptors
• Ligand gated ion channels / Ionotropic receptors


  the extracellular portion usually contains the ligand-binding site

  channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds

  examples:

  GABA receptor = Cl channel = increased Cl influx = hyperpolarization = inhibitory, relaxation, depression

  Nicotinic receptor = Na channel = increased Na influx = depolarization = excitatory, stimulation, muscle contraction

  hyperpolarization: Cl and K

  depolarization: Na and Ca
• G protein coupled receptors / Metabotropic receptors


  Largest family, aka 7-TM receptors
• G protein coupled receptors / Metabotropic receptors

  • Extracellular domains determine ligand binding and selectivity
  • Intracellular loops mediate the receptor interaction with its effector molecule, a guanine nucleotide binding protein (G protein), a peripheral membrane protein
• Examples of G protein coupled receptors

  • Adrenergic receptors
  • Nicotinic receptors
• a1 receptor


  Gq = activates phospholipase C = producing IP3 and DAG = vasoconstriction
• a2 receptor


  Gi = inhibits adenylyl cyclase = decreases the production of cAMP = decreased NE release
• b1 receptor

  Gs = activates adenylyl cyclase = increases the production of cAMP = increased heart rate and glandular secretion (bronchodilation)
• b2 receptor

  Gs = activates adenylyl cyclase = increases the production of cAMP = increased heart rate and glandular secretion (bronchodilation)
• M1 receptor


  Gq = activates phospholipase C = increased production of IP3 and DAG = vasoconstriction
• M2 receptor

  Gi = inhibits adenylyl cyclase = decreased production of cAMP = decreased NE release
• M3 receptor


  Gq = activates phospholipase C = increased production of IP3 and DAG = vasoconstriction
• Enzyme linked receptor / Tyrosine kinase receptor


  processes:

  drug binding

  dimerization = dimer formation (2 parts)

  phosphorylation = enzyme: kinase - transfer of phosphate; can substantially modify the structure of the target protein thereby acting as a molecular switch

  examples:

  insulin receptor = activates tyrosine kinase = stimulation of glucose reuptake

  atrial natriuretic factor receptor = increases guanylyl cyclase = increases sodium excretion
• Nuclear receptor

  entirely intracellular

  drug must be lipophilic (can penetrate the cell membrane)

  drug interacts to the DNA --> gene transcription

  targeted by: sex hormones, glucocorticoids, mineralocorticoids

  types:

  type 1 = steroid receptors = with CPPP molecules

  type 2 = non steroid receptors = example: Vit A and D
• location of type 1 receptors

  cell membrane
• location of type 2 receptors

  cell membrane
• location of type 3 receptors

  cell membrane
• location of type 4 receptors

  nucleus
• main action of type 1 receptors

  ion flux
• main action of type 2 receptors

  secondary messengers (cAMP, DAG, IP3)
• main action of type 3 receptors

  phosphorylation
• main action of type 4 receptors

  gene transcription
• response of type 1 receptors

  millisecond (fastest)
• response of type 2 receptors

  seconds
• response of type 3 receptors

  minutes
• response of type 4 receptors

  hours or days