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Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
Basic principles
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Basic principles

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  • 1. Introduction
  • 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.  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.  Vary from MW 7 (Li) to over MW 50,000 (thrombolytic enzymes) Majority have MW 100-1000
  • 5.  Very strong covalent bonds Weaker electrostatic bonds Much weaker interactions (H-bonds, van der Waals, hydrophobic bonds)
  • 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.  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.  Predicts the rate of movement of molecules across a barrierRate = (C1 – C2) x Permeability coefficient x Area Thickness
  • 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.  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.  “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. Blood Membranes of Urine pH 7.4 the nephron pH 6.0 Lipid diffusion NH3 NH3H+ H+ NH4+ NH4+
  • 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. 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. Intravenous Instantaneous and complete absorption Potentially more dangerous if administration is too rapid (high blood levels is reached)
  • 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. Subcutaneous Slower absorption than intramuscular First-pass metabolism is avoided Large-volume bolus doses are less feasible Applicable to heparin
  • 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. 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. 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. 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. Transdermal Involves application to the skin for systemic effect Absorption usually occurs very slowly First-pass effect is avoided
  • 23.  SIZE OF THE ORGAN – determines the concentration gradient between blood and the organ - larger organs can take up more (eg. muscles)
  • 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.  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.  BINDING – binding of a drug to macromolecules in blood or tissue compartment will tend to increase its concentration in that compartment
  • 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.  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.  FIRST-ORDER ELIMINATION Rate of elimination is proportionate to concentration Plasma concentration decreases exponentially with time Drugs have a characteristic half-life
  • 30. FIRST-ORDER ELIMINATION
  • 31.  ZERO-ORDER ELIMINATION Rate is constant regardless of concentration Plasma concentration decreases linearly Typical of ethanol and aspirin at toxic levels
  • 32. ZER0-ORDER ELIMINATION
  • 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.  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. 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.  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.  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.  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.  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. 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.  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.  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.  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.  Liver Kidneys Other tissues (blood, intestinal wall)

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