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Pharmacodynamics Pharmacodynamics Presentation Transcript

  • Saddam Ansari3rd yearTbilisi State Medical UniversityPharmacodynamics
  • Objectives Pharmacodynamics Major Receptor Families Dose –Response Relationships Quantal Dose – Response Relationships
  • PharmacodynamicsStudy of the biochemical andphysiological effects of drugs on theBodyMicroorganismsParasites within or on the body andMechanisms of drug action and therelationship between drugconcentration and effect
  • Continued… “Action of Drugs on the Body” Abbreviated as PDEffects on the Body (when drugs acts on body)??? Stimulating action Depressing action Blocking action Exchanging action Direct beneficial chemical reaction Direct harmful chemical reaction
  • Continued…Desired Effect Cellular membrane disruption Chemical reaction with downstream effects Interaction with enzyme proteins Interaction with structural proteins Interaction with carrier proteins Interaction with ion channels Ligand binding to receptors
  • Continued…Undesirable effects Increased probability of cell mutation(carcinogenic activity) Interaction (additive, multiplicative, ormetabolic) Induced physiological damage, or abnormalchronic conditions
  • Receptor Receptor is a molecule found on the surface of acell, which receives specific chemical signals fromneighbouring cells or the wider environmentwithin an organism.
  • Ligands Is a substance that forms a complex with abiomolecule to serve a biological purpose. “Signaltriggering molecules”
  • Ligand - Receptor Complex
  • Major Receptor Families Ligand-gated ion channels G protein- coupled receptors Enzyme-linked receptors Intracellular receptors Spare receptors Desensitization of receptors
  • Ligand-gated ion channels(LGICs)Are one type of ionotropic receptor or channel-linkedreceptor. They are a group of transmembrane ionchannels that are opened or closed in response tothe binding of a chemical messenger (i.e., aligand),such as a neurotransmitter.An ionotropic receptor, when activated, directlyaffects the activity of a cell by directly opening ionchannels.
  • Continued…Metabotropic receptor influences theactivity of a cell indirectly by firstinitiating a metabolic change in the cell.This metabolic change may ultimatelyaffect the opening or closing of an ionchannel or may alter some other activityof the cell such as protein transcription.
  • G protein-coupled ReceptorsG protein-coupled receptors (GPCRs),also known as : seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR)
  • Continued… Comprise a large protein family oftransmembrane receptors that sense moleculesoutside the cell and activate inside signaltransduction pathways and, ultimately, cellularresponses
  • Classes of GPCRs Class A (or 1) (Rhodopsin-like) Class B (or 2) (Secretin receptor family) Class C (or 3) (Metabotropic glutamate/pheromone) Class D (or 4) (Fungal mating pheromone receptors) Class E (or 5) (Cyclic AMP receptors) Class F (or 6) (Frizzled/Smoothened)
  • Second Messengers Second messengers are molecules that relaysignals from receptors on the cell surface totarget molecules inside the cell, in the cytoplasmor nucleus. They relay the signals of hormones likeepinephrine (adrenalin), growth factors, andothers, and cause some kind of change in theactivity of the cell.
  • Types of Second MessengerHydrophobic molecules: water-insolublemolecules, like: diacylglycerol,andphosphatidylinositols,are membrane-associated anddiffuse from the plasma membrane intothe intermembrane space where theycan reach and regulate membrane-associated effector proteins
  • Continued…Hydrophilic molecules: water-solublemolecules, like: cAMP,cGMP,IP3, andCa2
  • Continued…Gases:nitric oxide (NO)carbon monoxide (CO) andhydrogen sulphide (H2S) (whichcan diffuse both through cytosoland across cellular membranes.)
  • Properties of SecondMessengers They can be synthesized/released and brokendown again in specific reactions by enzymes orion channels. Some (like Ca2+) can be stored in specialorganelles and quickly released when needed. Their production/release and destruction can belocalized, enabling the cell to limit space and timeof signal activity.
  • Enzyme-linked Receptors An enzyme-linked receptor is a transmembranereceptor, where the binding of an extracellularligand causes enzymatic activity on theintracellular side. They have two important domains: Extra-cellular ligand binding domain Intracellular domainThe signaling molecule binds to the receptoroutside of the cell and causes aconformational change on the Catalyticfunction located on the receptor inside of thecell
  • Examples of Enzymatic Action Receptor tyrosine kinase, as in fibroblastgrowth factor receptor. Most enzyme-linkedreceptors are of this type Serine/threonine-specific protein kinase, as inbone morphogenetic protein Guanylate cyclase, as in atrial natriureticfactor receptor
  • Intracellular Receptors Intracellular receptors are receptors locatedinside the cell rather than on its cell membrane. Examples are the class of nuclear receptorslocated in the cell nucleus and the IP3 receptorlocated on the endoplasmic reticulum. The ligands that bind to them are usuallyintracellular second messengers like (IP3) andextracellular lipophilic hormones like steroidhormones.
  • Intracellular Receptors : TypesSteroid hormone receptor:Sex hormone receptors (sexhormones) Estrogen receptor (α and β) Androgen receptor (one type)Vitamin D receptor (vitamin D, onetype)Glucocorticoid receptor(glucocorticoids, one type)Mineralocorticoid receptor(mineralocorticoids, one type)
  • Continued… Thyroid hormone receptor (α and β) Retinoic acid receptor (vitamin A and relatedcompounds); Peroxisome proliferator-activated receptors(PPARs, α, γ and δ) Retinoid X receptor Farnesoid X receptor Liver X receptor Constitutive androstane receptor
  • Spare Receptors Term used to describe the situation in whichmaximum tissue response occurs when not all thereceptors of the tissue are occupied by the drug
  • Desensitization of Receptors The rapid signal attenuation in response tothe stimulation of cell by agonists or anantagonists. Or, decrease in response due to overadministration of durgs Adptation Refractoriness Down regulationIt is of 2 types….