Basic Principles II

Basic Principles II

1. Drug Transport

   • Has to pass through double and single
     • Double
       • capillary endothelial cells
     • Single
       • Cell Membrane
   • Processes
     • Passive Processes
       • Follow concentration gradient or hydrostatic pressure
       • Simple Diffusion
         • Affected by...
           • Lipid Solubility
           • Size
           • Degree of Ionization
       • Facilitated Diffusion
         • uses carrier protein
         • selective
       • Filtration
         • driven by hydrostatic pressure
         • drug size is limiting
     • Active Processes
       • Active Transport
         • Uses carrier
       • Micropinocytosis
         • transported in pinched off packets of membrane

2. Weak Electrolyte Drugs

   • Forms
     • Nonionized Forms
       • Diffuse
       • Lipid Soluble
       • Concentration Gradient
     • Ionized Forms
       • Do not diffuse
       • Weak acids and bases
     • pKa
       • determines ratio of ionized to non-ionized form at a particular pH
       • Henderson-Hasselbach Equation
   • Weak Acid Drugs
     • Nonionized in Stomach (pH=1.4)
     • Ionized in Plasma (pH=7.4)
   • Weak Base Drugs
     • Ionized in Stomach
     • Nonionized in Plasma (pH=7.4)
     • Generally won't be absorbed in GI tract

3. Drug Administration

   • Routes of Administration
     • Enteral
       • Portion of GI tract
       • Oral
         • A: ease, safety, self-administration, cheap, prolonged absorption causing prolonged effect
         • D: slow, unpredictable absorption, may cause irritation, destroyed by gastric acid/enzymes, met by liver (first pass, not available for all pt.
       • Rectal
         • A: useful for infants comatose, vomiting patient, useful for foul-smelling, distasteful drugs, drugs destroyed by upper GI tract, avoids met by liver, local action in rectum
         • D: poor compliance, absorption erratic/incomplete, possibility of rectal irritation
       • Sublingual
         • A: by-passes liver when absorbed, rapid absorption
         • D: must be solute in saliva, not gross, good pKa for absorption, small tablets
       • Factors
         • form, food in stomach, illness, blood flow
     • Paraenteral
       • avoids GI tract
       • IV
         • A: rapid effect, can watch response and titrate dose, all enters circulation, replace oral, for irritating drugs, given in large amounts of fluid, infusion and continuous, hypertonic solutions
         • D: cost, skill in administration, risk of infection, possible allergy, embolus formation risk, cardiovascular effects if too quick, pain
       • IA
         • A: admin of radioopaque material, high concentration of drug going to local area
         • D: same as IV
       • IM
         • A: when oral not available, less variable absorption, less painful, more rapid than subcu, possible slowing of absorption to extend effect
         • D: pain, sterile technique, possible local necrosis, lag period before effect onset, accidental IV injection possible, can't use after anticoag therapy
       • Subcutaneous
         • A: absorption slower than IM, longer effect, see IM
         • D: See IM
       • Intrathecal
         • A: when local effect on CNS required and other route unsatisfactory
         • D: Skill, danger of spinal cord injury
       • Topical
         • A: for local action on or under skin/membrane, non-invasive
         • D: Difficulty of absorption through skin, possible excessive absorption through membrane and systemic toxicity
       • Inhalation
         • A: rapid absorption for systemic action, high concentration, self administration
         • D: Possible excessive absorption and systemic toxicity, poor regulation of dosage, irritation of pulmonary
       • Factors
         • blood flow, heat, cold, illness, form
   • Considerations
     • Use of meds (home or clinic)
     • Acute vs. Chronic
     • Rapidity of onset of desired action
     • Target Organ
   • First Pass Effect
     • 1) drug administered by mouth
     • 2) Drug enters GI tract
     • 3) active drug is absorbed from stomach and small intestine
     • 4) high blood concentration of free drug is in hepatic portal vein (before liver metabolism
     • 5) Low blood concentration of free drug is systemic arterial or venous circulation (after liver metabolism)
   • Bioavailability
     • Fraction of dose available for biologic action
       • First pass
       • Variable absorption
     • Measured by comparing area under the curve for oral dose form vs. intravenous dose form
     • Greater bioavailability, the longer the effect
     • To predict plasma concentration...
       • Cp=Dose/Vd
       • Cp=(F*Dose)/Vd
         • F is fraction absorbed
     • Important for...
       • drugs that are potent in small doses
       • drugs for serious illnesses
       • changes in drug manufacturer