pharmacodynamics I-II

  1. JL a 26 yr old female, visits the physician in early spring with complaints of sneezing, itching eyes, and stuffy nose. The physician advises JL to take an OTC antihistamine with decongestant, fexofenadine D (similar to allegra D). Two weeks after starting the medication, she reports good relief of her symptoms.
    1. How are receptors involved in JL's symptoms?
    2. What signaling pathways are activated?
    3. What pharmacodynamic mechanisms does fexofenadine D utilize to alleviate her symptoms?
    4. What type of drug (antagonsit, agonist, etc.) is fexofenadine?
    5. What type of drug is represented by the "D" and what type of pharmacological agent is it?
    • 1. histamine receptors-excess production of the agonist histamine caused JL's symptoms which stimulated this family of receptors; adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors
    • 2. overstimulation of receptors or pathways--excess of histamine in JL's case
    • 3. binds to adrenergic receptors?
    • 4. competitive antagonist?
    • 5. adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors
  2. Receptors:
    • biological macromolecules that reside in the plasma membrane, or intracellular compartment
    • a receptor activates a particular pathway, enzyme, or protein within the cell, when it senses a signal
    • histamine receptors--excess production of the agonists histamine cause JL's symptoms, which stimulated this family of receptors
    • Adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors
    • the signal molecule is generally called a ligand or agonist
  3. ligand or agonist:
    the signal molecule
  4. effector:
    is a system, pathway, enzyme, or molecule that is activated in response to receptor binding, and intiates a response witin a cell
  5. Gs:
    • activates calcium channels
    • activates adenyl cyclase
    • increases cAMP
  6. Gi:
    • activates potassium channels
    • inhibits adenyl cyclase
    • decreases cAMP
  7. Go:
    inhibits calcium channels
  8. Gq:
    • activates phospholipase C
    • raises IP3 levels in the cells
    • increases intracellular free calcium
    • increases DAG
    • activates PKC
  9. G 12/13:
    interacts with many different ion transporters
  10. Biological drug targets:
    • Receptors and signaling pathways:
    • neurotransmitters (glutamate, serotonin)
    • insulin and other growth factors
    • histamine
    • hormones (glucocorticoids, estrogen)
    • adernegic receptors
    • opiod receptors
    • Enzymes:
    • cholinesterase
    • cyclooxygenase
    • monoamine oxidase
    • DNA topoisomerase
    • other macromolecules:
    • transport proteins
    • membrane lipids
    • nucleic acids
    • antibodies
    • new generation drugs
    • ion channels:
    • calcium channels
    • potassium channels
    • sodium channels
    • water channels
  11. Drugs, receptors, and signal transduction pathways:
    • drugs exert their effects by interacting with endogenous receptors and/or target molecules
    • receptor interactions
    • receptor interactions coordinate cell/organ/system function, using endogenous ligands
    • many drugs interat with these receptors as their mechanism of action
    • there are no specific "drug receptors"--receptors bind endogenous ligands
    • drugs utilize these receptors and "mimic" endogenous ligands to exert their pharmacologic effects
    • in some cases (opiods, anadamide) we knew about the drug before we knew what the endogeous ligand was !
    • some classes of drugs interact with target molecules that are not receptors, per se. (i.e. antacids, enzyme inhibitors, others)
  12. Ion channels as drug targets:
    • activation of specific ion channels change ion gradients, which is used to alter diverse body functions
    • contraction/relaxation of vascular smooth muscle to regulate blood pressure
    • contraction of skeletal muscle
    • secretion of insulin by the pancreas
    • ion channels are classified by how they are gated (regulated)
    • activation by ligand binding-ligand gated ion channels
    • activation by voltage changes across the membrane--voltage gated ion channels
    • activation by second messenger systems--second messenger gated ion channels
    • ion channels are generally specific for a given ion
  13. Enzymes as drug targets:
    • many drugs have enzymes as their targets
    • drug either activates or inhibits the enzyme
    • examples:
    • cyclooxygenase--synthesizes inflammatory mediators, inhibited by aspirin
    • monoamine oxidase--degrades amine neurotransmitters, target of the antidepressent seligilene
    • cholinesterase--degreades acetylcholine at the synapses, target of the AD drug, donepezil
    • DNA topoisomerase-target of the antibiotic ciproflaxcin
  14. Other drug targets:
    • drug targets may include structural proteins, such as tubulin the target for antineoplastic drugs
    • drug targets may include circulating proteins, such as Omalizumab, an antibody to IgE
    • drug targets may include molecular transporters, such serotonin reuptake systems, the targets of some of the new antidepressants
    • new drug targets are being found every day
    • the science or target identification and validation
    • currently sought after targets include
    • new targets for alzheimer's
    • new targets for parkinson's disease
    • new targets for cancer
    • nanopharmaceuticals
  15. Cellular regulation of drug-target interactions:
    • interaction of drugs with targets can have a testing impact on a cell due to innate cellular mechanisms that prevent overstimulation
    • tachyphylaxis:
    • drug effects diminshes with time
    • homologous--only 1 type of receptor affected
    • heterologous--multiple receptor types are affected, possibly due to converging second mesenger or effector systems
    • receptor inactivation
    • receptor looses ability to respond to stimulation
    • beta adrenegic receptor is phosphorylated and inactivated after repeated stimulation
    • down regulation
    • decrease in the number of receptors, increase in degradation rate, decrease in synthesis
    • the beta adrenergic receptor is also down regulated with repeated stimulation
    • refractory receptors
    • after a receptor is stimulated, a period of time is required before the next interaction can produce an effect
    • voltage-gated sodium channels in neurons have a refractory period
  16. Spare receptors:
    • a single ligand/receptor complex can "turn on" many G proteins
    • multiplies original signal
    • a single activated G protein can persist in activated state, often for a longer time period than the ligand is bound to the receptor
    • because of this prolongation and amplification, only a fraction of the total number of receptors for a specific ligand need to be occupied to produce a maximal effect in a cell
    • the pool of receptors that are unstimulated are "spare receptors"
    • insulin receptor--99% of a given cell's insulin receptors are spare
    • only 1% required for maximal response
    • large functional reserve to ensure that adequate amounts of glucose enter the cell
    • the heart--only 5-10% of the beta adrenergic receptors are spare
    • 90-95% are used for maximal response
    • almost all receptors need binding for maximum contractility
    • little functional reserve here, important for the failing heart
  17. Kd:
    is the concentration of ligand that causes 50% receptor occupancy
  18. Drug potency:
    a measurement of the amount of drug necessary to produce an effect of a given magnitude
  19. the smaller the Kd, the more ________ the drug
  20. The EC50:
    the "effective concentration needed to achieve a 50% maximal response
  21. Drug efficacy:
    the maximum achievable response to a drug
  22. ED50:
    is the drug dose which 50% of the patients exhibit a response, and 50% of the patients do not exhibit the response
  23. LD50:
    lethal dose 50 the drug dose that kills 50% of patients
  24. TD50:
    toxic dose 50 the drug dose that causes toxicity in 50% of patients note,, there may be series of TD50 for a single drug, one for each different toxic response
  25. Therapeutic window:
    a range of doses (concentrations) of a drug that elicit a therapeutic response, without unacceptable side effects (toxicity)
  26. Therapeutic index:
    therapeutic window is quantified by this
  27. Competitive antagonist:
    • binds reversibly to the active site of a receptor or drug target, and inhibits agonist binding
    • an antagonist does not produce the conformational change necessary for receptor activation
    • an antagonist maintains the receptor in the inactive state
    • the presence of a competitive antagonist reduces the potency of an agonist
    • the efficacy is not affected (antagonist can always be "competeted away" by more agonist)
    • competitive antagonists shift the dose response curve to the right
    • ex. antihistamine and pravastin
  28. noncompetitive antagonist:
    • may bind to active site or allosteric site
    • binding is strong--may be irreversible and with high affinity
    • cannot be "competed" away with high concentrations of agonist
    • the presence of a competitive antagonist reduces the efficacy of an agonist
    • noncompetitive agonists remove receptors from the available pool, hence the reduction in efficacy
    • ex. aspirin and clopidogrel (plavix)
  29. Partial agonist:
    • binds to a receptor at the active site, but produces only a partial response
    • in the presence of a full agonist (or endogenous agonist) the partial agonist reduces the maximum response
    • acts somewhat like a competitive antagonist
    • aka partial antagonists or mixed agonist/antagonist
    • butyl and hexyl are full agonists with different potencies
    • heptyl and octyl are partial agonists
    • ex. pindolol
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pharmacodynamics I-II