Pcol L1 (pre-lecture slides)

• 3 principles of pharmacology (disease/cause, drug, active ingredient, dose)

  1. each disease has a specific cause for which there is a specific remedy

  2. each natural remedy has an identifiable component which is responsible for its efficacy

  3. size of dose determines degree of response
• Who is credited with "the dose makes the poison"

  - concept that distinguishes pharmacology from toxicology

  - basis of the dose-response relationship

  - remedy vs poison

  Paracelsus
• true or false: Diethyl barbituric acid was the first designed based on its structure

  true
• 1st dept of pharmacology

  umich
• he classified drugs by their action on organ functions, rather than botanical origins

  - "systemic exploration of experimental pharmacological methods"

  - investigate MOA

  - use of stat analysis

  Rudolph Buchheim "Rudolph ..organ function"
• He isolated morphine from the opium poppy plant

  Friedrich Serturner..."turned poppy plant into morphine"
• Active Ingredient in Foxglove plant?

  who discovered it?

  Digoxin

  William withering

  - found treatment of dropsy with foxglove plant

  - described treatment of 158 patients w/ foxglove extract

  - Primary side effect noted for foxglove plant was vomiting

  - digitalis purpurea
• He isolated an alkaloid muscarine from the Amanita mushroom

  Oswald Schmiedeberg
• He was a student of Schmiedeberg, was known for purification of epinephrine, pituitary hormones, and insulin

  John Jacob Abel
• Pharmacodynamics


  What the drug does to the body
• Pharmacokinetics


  study of drug absorption, distribution, metabolism, excretion (ADME)
• Pharmacology=


  pharmacokinetics + pharmacodynamics; interaction of chemicals with biological systems to yield therapeutic or other beneficial effects
• Agonists: drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds.

  
  

  Primary agonist = drug binds to same site on the receptor as the endogenous ligand. This specific site is called an orthosteric binding site.

  
  

  allosteric agonist= drug binds to dif site on receptor as the endogenous ligand. (this site is called allosteric/allotopic binding site). these agonists will still mimic the effects of primary agonists
• competitive antagonist binds at ___ site as agonist

  same
• enzyme regulators that bind an allosteric site are

  non-competitive inhibitors
• Occupancy Theory**

  "the response of a tissue to a drug/ligand (exogenous) is a function of the # of receptors bound or occupied to the drug "

  
  

  The intensity of a drugs response is proportional to the number of receptors occupied, maximal response occurs when all receptors are occupied.

  1. site on the receptor where a drug binds = binding site
  2. the concentration of the drug/ligand is an important factor for the extent of receptor binding
  3. typically need to reach a threshold of receptor occupancy by drug/ligand to see effect in the tissue = cumulative nature of response
• Warfarin (anticoagulant drug)

  • S enantiomer is 4x more potent than R due to stronger interactions at the binding site of vitamin K epoxide reductase. S>R better @ binding
  • ex. Which enantiomer of warfarin is more potent inhibitor vitamin K epoxide reductase? S
• Sotalol (anti arrhythmic drug)**


  The D and L enantiomers=equipotent K+ channel blockers

  
  

  L = more potent beta adrenergic antagonist
• Amino acids that directly interact with the lipid binary are __hydrophillic/phobic__ in nature .

  hydrophobic.

  
  

  hydrophilic = cytosol

  
  

  Binding sites possess unique chemical properties: 3D structure, shape, reactivity
• Drug-Receptor Bonds (lowest to highest)

  van der waals< Hydrogen < Ionic < Covalent
• BOND TYPES

  Covalent - 2 bonding atoms share e-

  
  

  Ionic - atoms w/ excess of e- are attracted to atoms w/ a deficiency of e- =overall + charge

  
  

  
  

  Hydrogen - H atoms, O, N, S

  
  

  Van Der Waals - shifting e- densities that generate +/-
• agonists vs antagonists?

  agonists - enhance activity

  antagonists - decrease activity/response
• Drug-Receptor Interaction **

  Affinity - how well a drug binds to a receptor or the tightness of interaction

  
  

  Intrinsic activity -ability of a drug to produce a measurable effect after binding a receptor

  
  

  Selectivity - how well a drug binds the intended target versus other proteins in the body

  
  

  Number - how many receptors are available for binding
• Lock & Key Model


  - older, static model of drug-receptor binding

  - does not consider conformational changes in the receptor upon drug binding

  - shape of the substrate and the confirmation of the active site are COMPLEMENTARY

  (perfect fit already, no change )
• Induced Fit Model


  - binding of a drug to its receptor results in a conformational change in the receptor that enhances the affinity of the drug for the receptor

  
  

  - shape of the active site becomes complementary to shape of drug only after binding the receptor
• first true chemical designed?

  diethyl barbituric acid or barbital or veronal. used as a sleeping aid form 1903-1950s. bayer in Germany. hypnotic drugs(tranquilizers)
• selected characteristics of pharmacological agents (4)

  intended for specific purposes, usually either to prevent/treat illness, administered in an appropriate physical form, specific dosing regimens are required. (why, how, what)
• toxicology: interaction of chemicals with biological systems to yield adverse effects ; meaning harmful, unfavorable, unintended.
• most drugs work via receptors.
• drug receptor or target is a cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response. drugs commonly alter the rate or magnitude of an intrinsic cellular response (cell's internal mechanisms that are activated in response to various stimuli. like virus, stress, environment) rather than create new ones.
• noncompetitive antagonists: interacts with other sites on the receptor ...allosteric antagonism
• functional antagonists: indirectly inhibit the cellular or physiological effects of the agonist
• 4 drug properties that affect binding of drug to its receptor: hydrophobicity, ionization state (pka), conformation, stereochemistry.
• Labetalol (anti-hypertensive drug): 4 diastereometers.

  R,R -potent B1 antag, partial b2 agon

  S,R S,S -little or no beta antagonist, but a1 antag

  R,S - devoid of adrenergic blocking activity / n/a
• Most receptors are proteins.

  Primary= sequence of amino acids

  Secondary= H+ and O- interactions

  Tertiary= interactions of amino acids that are far apart using ionic bonds and covalent disulfide links

  Quaternary= interactions between 2+ independent protein subunits
• Imantinib : prevents phosphorylation of a critical activation loop in BCR-Abl Kinase --> prevents catalytic activity and promotes cancer growth.

  intermolecular interactions: H bonds and VDW
• intrinsic actvity- ability of ligand to have a biological effect (even if its reducing/inhibiting neuronic activity)

  antagonist- don't do anything by themselves; prevent agonist from working