Basic principles


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Basic principles

  1. 1. Introduction
  2. 2.  the body of knowledge concerned with the action of chemicals (drugs) on biologic systems Medical Pharmacology – use of drugs in the prevention, diagnosis, and treatment of disease, especially in humans Toxicology – undesirable effects of drugs on biologic systems
  3. 3.  Commonly include: inorganic ions nonpeptide organic molecules small peptides and proteins nucleic acids lipids Carbohydrates Often found in plants and animals Many partially or completely synthetic
  4. 4.  Vary from MW 7 (Li) to over MW 50,000 (thrombolytic enzymes) Majority have MW 100-1000
  5. 5.  Very strong covalent bonds Weaker electrostatic bonds Much weaker interactions (H-bonds, van der Waals, hydrophobic bonds)
  6. 6.  1. AQUEOUS DIFFUSION – passive movement through the extracellular and intracellular spaces (usually through water-filled pores) 2. LIPID DIFFUSION – passive movement through membranes
  7. 7.  3. FACILITATED DIFFUSION – transport by special carriers across barriers - capacity-limited - may be inhibited 4. ENDOCYTOSIS, PINOCYTOSIS – permit transport of very large (peptides) or very lipid-insoluble molecules or complexes (small, polar molecules combined to special proteins)
  8. 8.  Predicts the rate of movement of molecules across a barrierRate = (C1 – C2) x Permeability coefficient x Area Thickness
  9. 9.  Weak bases – ionize when protonated; more water-soluble RNH3+ ⇋ RNH2 + H+ Water-sol. Lipid-sol. Weak acids – do not ionize when protonated; more lipid-soluble RCOOH ⇋ RCOO- + H+ Lipid-sol. Water-sol.
  10. 10.  can predict the fraction of molecules in the ionized state (water-soluble) if the pKa of the drug and the pH of the medium are known pKa - pH = log Protonated form Unprotonated form Clinically important when it is necessary to estimate or alter the partition of drugs between compartments of differing pH
  11. 11.  “Trapping” is a method for accelerating excretion of drugs. Nonionized form diffuses readily across the lipid barriers of the nephron Protonation will occur within the blood and urine Example: Pyrimethamine – pKa 7.0 >
  12. 12. Blood Membranes of Urine pH 7.4 the nephron pH 6.0 Lipid diffusion NH3 NH3H+ H+ NH4+ NH4+
  13. 13.  Rate and efficiency of absorption differ depending on a (1) drug’s route of administration, (2) blood flow, (3) concentration of drug at site of administration Bioavailability = The amount absorbed into systemic circulation divided by the amount of drug administered
  14. 14. Oral (swallowed) maximum convenience slower absorption and less complete drugs are subject to first-pass effect (a significant amount is metabolized in the gut wall, portal circulation, and liver before reaching systemic circulation)
  15. 15. Intravenous Instantaneous and complete absorption Potentially more dangerous if administration is too rapid (high blood levels is reached)
  16. 16. Intramuscular Often faster and more complete than oral Large volumes may be given if drug is not too irritating First-pass metabolism is avoided NOT applicable to anticoagulants (heparin) as this may cause bleeding
  17. 17. Subcutaneous Slower absorption than intramuscular First-pass metabolism is avoided Large-volume bolus doses are less feasible Applicable to heparin
  18. 18. Buccal and sublingual Permits direct absorption into systemic venous circulation Bypasses hepatic portal circulation and first- pass metabolism Fast or slow depending on physical formulation of drug
  19. 19. Rectal (suppository) Partial avoidance of first-pass effect (absorption from this location is partially into portal circulation) May cause significant irritation Drugs with unpleasant tastes may be administered rectally
  20. 20. Inhalation Offers delivery closest to the target tissue (respiratory diseases) Rapid absorption Convenient for drugs that are gases at room temperature (NO, N2O) or easily volatilized (anesthetics)
  21. 21. Topical Application to skin or mucous membrane of the eye, nose, throat, airway, or vagina for local effect Rate of absorption varies with area of application and drug’s formulation Usually slower than any of the previous routes listed
  22. 22. Transdermal Involves application to the skin for systemic effect Absorption usually occurs very slowly First-pass effect is avoided
  23. 23.  SIZE OF THE ORGAN – determines the concentration gradient between blood and the organ - larger organs can take up more (eg. muscles)
  24. 24.  BLOOD FLOW – determines the rate of uptake, although it may not affect the steady-state amount of drug in the tissue - well-perfused tissues (eg. brain, heart, kidneys, splanchnic organs) will often achieve high tissue concentrations sooner than poorly-perfused tissues (eg. fat, bone)
  25. 25.  SOLUBILITY – influences the concentration of the drug in the extracellular fluid surrounding the blood - example: some organs (like brain) have a high-lipid content; thus, very lipid-soluble anesthetic will diffuse into the brain tissue more rapidly and to a greater extent than a drug with low lipid-solubility
  26. 26.  BINDING – binding of a drug to macromolecules in blood or tissue compartment will tend to increase its concentration in that compartment
  27. 27.  Occurs primarily in the liver Conversion to a metabolite terminates drug action (a form of elimination) Prodrugs ( eg. Levodopa, minoxidil) are metabolized to become active Some drugs are not metabolized and continue to act until they are excreted
  28. 28.  Not the same as drug excretion Excretion is primarily by way of the kidneys, except anesthetic gases (lungs) Some drugs (diazepam) have active metabolites For drugs that are not metabolized, excretion is the mode of elimination A few drugs combine irreversibly with receptors, so disappearance from the bloodstream is not equivalent to termination of action
  29. 29.  FIRST-ORDER ELIMINATION Rate of elimination is proportionate to concentration Plasma concentration decreases exponentially with time Drugs have a characteristic half-life
  31. 31.  ZERO-ORDER ELIMINATION Rate is constant regardless of concentration Plasma concentration decreases linearly Typical of ethanol and aspirin at toxic levels
  33. 33.  Deals with effects of drugs on biologic systems RECEPTOR – specific molecules in the biologic system to which a drug binds to bring about change in function of the system AGONIST – drug that activates its receptor upon binding
  34. 34.  EFFECTOR – channel or enzyme that accomplishes the effect after activation by the receptor INERT BINDING SITE – component to which a drug binds without changing any function ANTAGONIST – drug that binds to receptor without activating it
  35. 35. 1. Competitive – can be overcome by increasing the dose of the agonist2. Irreversible – cannot be overcome by increasing the dose of the agonist3. Physiologic – counters the effects of another by binding to a different receptor and causing opposing effects4. Chemical - counters the effects of another by binding the drug and preventing its action5. Partial – binds to its receptor but produces a smaller effect at full dosage than a full agonist
  36. 36.  Maximal efficacy (Emax) The maximum effect an agonist can bring about regardless of dose Determined mainly by the nature of the receptor and its associated effector system
  37. 37.  Dose or concentration required to bring about 50% of a drug’s maximal effect (EC50) – in graded-dose response Determined mainly by affinity of the receptor for the drug Typical variables in *quantal dose-response: ED50 – median effective TD50 – median toxic LD50 – median lethal *minimum dose required to produce a specific response in each member of the population
  38. 38.  index of safety Dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. Eg. Theophylline: 8 – 18 mg/mL
  39. 39.  Distribution - the process by which a drug diffuses or is transferred from intravascular space to extravascular space (body tissues). These spaces are described mathematically as volume(s) of distribution. Volume of distribution is that volume of bodily fluid into which a drug dose is dissolved
  40. 40. The body is usually divided into two spaces, a central and a tissue compartment.Central volume (Vc) = blood in vessels and tissues which are highly perfused by blood. Vc = Dose / Peak serum level  Peak = Dose / Vc
  41. 41.  Peripheral volume (Vt) = sum of all tissue spaces outside the central compartment Vc + Vt = Vd Distribution volumes are important for estimating: Amount of drug in the body, Peak serum levels, and Clearance
  42. 42.  Volume of distribution (Vd) Vd = Amount of drug in the body Plasma drug concentration Clearance (CL) CL = Rate of elimination of drug Plasma drug concentration
  43. 43.  PHASE I REACTIONS - oxidation, reduction, deamination, and hydrolysis PHASE II REACTIONS - synthetic reactions that involve addition (conjugation) of subgroups to –OH, -NH2, and –SH on the drug molecule; - subgroups include glucoronate, acetate, glutathione, glycine, sulfate, and methyl groups
  44. 44.  Liver Kidneys Other tissues (blood, intestinal wall)