{"id":45616,"date":"2019-08-05T21:21:59","date_gmt":"2019-08-05T20:21:59","guid":{"rendered":"http:\/\/localhost\/wordpress\/?page_id=1370"},"modified":"2019-09-16T09:02:54","modified_gmt":"2019-09-16T09:02:54","slug":"pharmacokinetics-1-administration-absorption","status":"publish","type":"page","link":"https:\/\/educationexpress.uts.edu.au\/pharmacology\/pharmacokinetics-1-administration-absorption\/","title":{"rendered":"Pharmacokinetics 1: Administration & Absorption"},"content":{"rendered":"\n
\n

\n\nA\/Prof. Ken Rodgers School of Life Sciences\n\n<\/h1>\n<\/div><\/div>\n\n\n\n
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\n

Learning Objectives<\/strong><\/h2>\n\n\n\n
  • Understand the effect of pH partitioning and lipid solubility on drug absorption<\/li>
  • Describe factors affecting the absorption of drugs via oral administration especially first-pass metabolism<\/li>
  • Understand the suitability, limitations and precautions of various routes of administration<\/li>
  • Outline the concept of bioavailability<\/li><\/ul>\n<\/div><\/div>\n\n\n\n

    References<\/h2>\n\n\n\n
    • Rang HP, Dale MM, Ritter JM,  Flower R and Henderson G (2015) Pharmacology<\/em>, 8th Edition, Churchill Livingstone, Sydney.<\/li>
    • Absorption and distribution of drugs\u2013 Chapter 8<\/li><\/ul>\n\n\n\n
      <\/div>\n\n\n\n
      \n

      Drug Absorption<\/h1>\n<\/div><\/div>\n\n\n\n
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        <\/div>\n\n\n\n

        Absorbtion occurs mainly by diffusion through membranes<\/h2>\n\n\n\n
        • If a drug has a low lipid solubility it will be poorly absorbed from gut (eg tubocurarine<\/strong>)<\/li>
        • Exception: Very small molecules may be able to penetrate poses in the mebrane (rare)<\/li>
        • Exception: If a drug is similar to a natural molecule that is transported on a carrier it could be absorbed by carrier-mediated (pump) transfer (eg levodopa, fluorouracil)<\/li><\/ul>\n\n\n\n
          • \"\"<\/figure><\/li>
          • \"\"<\/figure><\/li><\/ul>\n\n\n\n
            <\/div>\n\n\n\n

            Passage of Drugs Across Membranes<\/h2>\n\n\n\n
            • Cell membranes form barriers between aqueous compartments in the body<\/li>
            • Cell membrane are relatively impermeable to ionised drugs<\/li>
            • Special carriers and endo\/exocytosis are probably not very important in drug absorption (few exceptions)<\/li>
            • Main process is probably pH partitioning<\/li><\/ul>\n\n\n\n
              • \"\"<\/figure><\/li>
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                <\/div>\n\n\n\n
                \n

                pH Partitioning<\/h1>\n<\/div><\/div>\n\n\n\n
                \"\"<\/figure>
                \n

                pH Partitioning <\/strong><\/h2>\n\n\n\n
                • Most drugs, or their salts, are weak acids\/bases<\/li>
                • Thus the proportion of ionised to non-ionised drug depends upon the pH<\/li>
                • Ionised drugs are not very lipid soluble \u2013 only non-ionised form of drug crosses membrane readily<\/li><\/ul>\n\n\n\n

                  <\/p>\n<\/div><\/div>\n\n\n\n

                  <\/div>\n\n\n\n
                  \"\"<\/figure>
                  \n

                  pH Partitioning <\/h2>\n\n\n\n
                  • Biological fluids (blood, stomach and intestinal contents, urine) have different pH values<\/li>
                  • The pH of the solution will change the amount of drug that is ionised and will affect how and where drug is absorbed, distributed and how well it is excreted<\/li>
                  • For weak acids and weak bases the  % ionisation is determined by the Henderson-Hasselbalch equation<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                    <\/div>\n\n\n\n

                    pH Partitioning<\/h2>\n\n\n\n
                    • \"\"<\/figure><\/li>
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                      \"\"<\/figure>
                      \n

                      pH Partitioning<\/h2>\n\n\n\n
                      • The degree of ionization is determined by the pK<\/em>a<\/sub> of drug and pH of the solution<\/li>
                      • If the pH of the solution is the same as the pKa of the drug then  50% will be ionised and 50% will be non-ionised.<\/strong><\/li>
                      • For acids:
                        • pK<\/em>a<\/sub> \u2013 pH = log ( [non-ionised] \/ [ionised] )<\/li>
                        • If pH = pKa then the log part of the equation = 0<\/li>
                        • We know that log 1 = 0 so  [non-ionised] \/ [ionised] must equal 1 so they must be the same<\/li><\/ul><\/li>
                        • For bases:
                          • pK<\/em>a<\/sub> \u2013 pH = log ( [ionised] \/ [non-ionised] )<\/li><\/ul><\/li><\/ul>\n\n\n\n

                            <\/p>\n<\/div><\/div>\n\n\n\n

                            <\/div>\n\n\n\n
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                              <\/div>\n\n\n\n

                              pH partitioning 4<\/h2>\n\n\n\n
                              • Eg. aspirin (weak acid), pK<\/em>a<\/sub> = 3.5<\/li><\/ul>\n\n\n\n
                                • \"\"<\/figure><\/li>
                                • \"\"<\/figure><\/li><\/ul>\n\n\n\n
                                  \"\"<\/figure>
                                  \n

                                  pH partitioning 5<\/h2>\n\n\n\n
                                  • Eg. pethidine (weak base), pK<\/em>a<\/sub> = 8.6<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                    <\/div>\n\n\n\n
                                    • \"\"<\/figure><\/li>
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                                      Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between urine, plasma and gastric juice according to their pH differences. Numbers represent relative concentrations (total plasma concentration = 100). It is assumed that the uncharged species in each case can permeate membranes separating the compartments, and therefore reaches the same concentration in all three. Variations in the fractional ionisation as a function of pH give rise to the large total concentration differences with respect to plasma. <\/p>\n\n\n\n

                                      pH Partitioning 6<\/h2>\n\n\n\n
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                                        <\/div>\n\n\n\n
                                        \n

                                        Applications of pH Partitioning<\/h1>\n<\/div><\/div>\n\n\n\n

                                        Applications of pH Partitioning 1<\/h2>\n\n\n\n
                                        • Alkalinisation of urine <\/strong>(NaHCO3<\/sub>): increases rate of excretion of weak acids (more ionised) eg phenobarbital<\/li><\/ul>\n\n\n\n
                                          • \"\"<\/figure><\/li>
                                          • \"\"<\/figure><\/li><\/ul>\n\n\n\n
                                            <\/div>\n\n\n\n

                                            Applications of pH Partitioning 2<\/h2>\n\n\n\n
                                            • Acidification of urine <\/strong>(NH4<\/sub>Cl): increases rate of excretion of weak bases (more ionised)<\/li><\/ul>\n\n\n\n
                                              • \"\"<\/figure><\/li>
                                              • \"\"<\/figure><\/li><\/ul>\n\n\n\n
                                                <\/div>\n\n\n\n
                                                \"\"<\/figure>
                                                \n

                                                Applications of pH Partitioning 3<\/h2>\n\n\n\n
                                                • Increasing plasma pH <\/strong>(NaHCO3<\/sub>): will shift weakly acidic drugs from the CNS to plasma (more ionised)<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                                  <\/div>\n\n\n\n
                                                  \"\"<\/figure>
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                                                  Summary: cellular barriers<\/h2>\n\n\n\n
                                                  • To traverse cellular barriers (e.g. gastrointestinal mucosa, renal tubule, blood-brain barrier, placenta), drugs have to cross lipid membranes.<\/li>
                                                  • Drugs cross lipid membranes mainly by (a) passive diffusion<\/li>
                                                  • The main factor that determines the rate of passive diffusion across membranes is a drug\u2019s lipid solubility (pH partitioning). Molecular weight is less important.<\/li><\/ul>\n\n\n\n

                                                    <\/p>\n<\/div><\/div>\n\n\n\n

                                                    <\/div>\n\n\n\n
                                                    \"\"<\/figure>
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                                                    Summary: pH Partitioning<\/h2>\n\n\n\n
                                                    • Many drugs are weak acids or weak bases; their state of ionisation varies with pH according to the Henderson-Hasselbalch equation.<\/li>
                                                    • Only the uncharged species (the protonated form for a weak acid, the unprotonated form for a weak base) can diffuse across lipid membranes; this gives rise to pH partition.<\/li>
                                                    • Weak acids tend to accumulate in compartments of relatively high pH (highly ionised)<\/li>
                                                    • Weak bases tend to accumulate in compartments of relatively low pH (highly ionised).<\/li>
                                                    • When the pH = Pka<\/sub> the weak acid\/base is 50% ionised<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                                      <\/div>\n\n\n\n
                                                      \n

                                                      Oral Administration & Absorption<\/h1>\n<\/div><\/div>\n\n\n\n
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                                                      The oral route of drug administration<\/h2>\n\n\n\n
                                                      • Oral route (enteral), p.o. (per os<\/em>)<\/strong><\/li><\/ul>\n\n\n\n
                                                        • 1. most common route<\/li>
                                                        • 2. usually safest<\/li>
                                                        • 3. most convenient<\/li>
                                                        • 4. most economical<\/li>
                                                        • Surface area, not pH partition, is main determinant of site of absorption \u2013 villi\/microvilli in small intestine > stomach<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                                          <\/div>\n\n\n\n

                                                          Rapid oral absorption<\/h2>\n\n\n\n
                                                          • So for rapid drug absorption, typically \u2026
                                                            • Take tablet with a large glass of water (eg 200 mL)<\/li>
                                                            • Take on an empty stomach eg at least half an hour before food (as long as gastric irritation is not a problem)<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                              <\/div>\n\n\n\n

                                                              First-pass metabolism<\/h2>\n\n\n\n
                                                              • 1. First-pass metabolism
                                                                • Before entering the systemic circulation, blood leaving the GI tract passes through the liver<\/li>
                                                                • Thus, drugs that are highly metabolised by the liver may attain very low circulating levels relative to those attained after parenteral administration<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                  • \"\"<\/figure><\/li>
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                                                                  • \"\"<\/figure><\/li><\/ul>\n\n\n\n
                                                                    <\/div>\n\n\n\n
                                                                    \n

                                                                    Difficulties with Oral Absorption<\/h1>\n<\/div><\/div>\n\n\n\n

                                                                    First-pass metabolism<\/h2>\n\n\n\n
                                                                    • Difficulties with oral route 1<\/strong><\/li>
                                                                    • 1. First-pass metabolism
                                                                      • Before entering the systemic circulation, blood leaving the GI tract passes through the liver<\/li>
                                                                      • Thus, drugs that are highly metabolised by the liver may attain very low circulating levels relative to those attained after parenteral administration<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                        • \"\"<\/figure><\/li>
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                                                                        • \"\"<\/figure><\/li><\/ul>\n\n\n\n
                                                                          <\/div>\n\n\n\n

                                                                          Irregular absorption<\/h2>\n\n\n\n
                                                                          • Difficulties with oral route 2<\/strong><\/li>
                                                                          • 2. Irregular absorption depends on stomach contents
                                                                            • delayed gastric emptying time<\/li>
                                                                            • altered stomach pH due to food<\/li>
                                                                            • decreased splanchnic blood flow in CHF<\/li>
                                                                            • complex formation of drug with food products (eg tetracyclines <\/em>with milk)<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                              <\/div>\n\n\n\n

                                                                              Absorption of alcohol<\/h2>\n\n\n\n
                                                                              \"Absorption<\/figure><\/div>\n\n\n\n
                                                                              <\/div>\n\n\n\n
                                                                              \"\"<\/figure>
                                                                              \n

                                                                              Difficulties with oral route 3<\/h2>\n\n\n\n

                                                                              3. Gastrointestinal irritation eg aspirin
                                                                              4. Low pH may inactivate certain drugs eg penicillins, insulin
                                                                              5. Particle size (small = more rapid absorption)
                                                                              (eg see digoxin graph)
                                                                              6. Requires patient compliance<\/p>\n<\/div><\/div>\n\n\n\n

                                                                              <\/div>\n\n\n\n
                                                                              \n

                                                                              Bioavailability<\/h1>\n<\/div><\/div>\n\n\n\n
                                                                              \"\"<\/figure>
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                                                                              Oral bioavailability<\/h2>\n\n\n\n
                                                                              • All the above factors influence oral bioavailability<\/strong>
                                                                                • Fraction of orally administered drug that reaches the systemic circulation<\/strong><\/li>
                                                                                • Two drugs with identical chemical composition that yield different blood concentrations and different effectiveness, differ in bioavailability (and are not bioequivalent)<\/li>
                                                                                • Varies between individuals<\/li><\/ul><\/li><\/ul>\n\n\n\n

                                                                                  <\/p>\n<\/div><\/div>\n\n\n\n

                                                                                  \"Oral<\/figure><\/div>\n\n\n\n
                                                                                  <\/div>\n\n\n\n

                                                                                  Overview of bioavailability<\/h2>\n\n\n\n

                                                                                  eg bioavailability of morphine via oral administration is only 20-33% when compared to IV administration<\/p>\n\n\n\n

                                                                                  • Intravenous: 100% by definition
                                                                                    Intramuscular: 75 to <100%
                                                                                    Subcutaneous: 75 to <100%
                                                                                    Oral: 5 to <100%
                                                                                    Rectal: 30 to <100%
                                                                                    Inhalation: 5 to <100%
                                                                                    Transdermal: 80 to <100%<\/li><\/ul>\n\n\n\n
                                                                                    <\/div>\n\n\n\n
                                                                                    \n

                                                                                    Other forms of drug administration<\/h1>\n<\/div><\/div>\n\n\n\n
                                                                                    \"\"<\/figure>
                                                                                    \n

                                                                                    Sublingual (SL)<\/h2>\n\n\n\n
                                                                                    • Under the tongue<\/li>
                                                                                    • Rapid absorption
                                                                                      • eg. glyceryl trinitrate<\/li><\/ul><\/li>
                                                                                      • Avoids exposure of drug to gastric pH<\/li>
                                                                                      • Avoids first-pass metabolism<\/li>
                                                                                      • Taste could be an issue<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                                                                        <\/div>\n\n\n\n

                                                                                        Intravenous<\/h2>\n\n\n\n
                                                                                        • Absorption pattern
                                                                                          • Precise, accurate and potentially immediate effects (absorption phase is bypassed)<\/li>
                                                                                          • Suitable for large volumes and mixtures<\/li><\/ul><\/li>
                                                                                          • Special Utility
                                                                                            • Valuable for emergency use, permits titration of dose<\/li>
                                                                                            • Usually required for high molecular weight protein and peptide drugs (eg. tPA)<\/li><\/ul><\/li>
                                                                                            • Limitations and precautions
                                                                                              • Greater risk of adverse effects
                                                                                                • High concentration attained rapidly<\/li>
                                                                                                • Risk of embolism<\/li><\/ul><\/li>
                                                                                                • Must inject solutions slowly as a rule<\/li>
                                                                                                • Not suitable for oily solutions or poorly soluble drugs<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                                                  <\/div>\n\n\n\n

                                                                                                  IM and subcutaneous injection<\/h2>\n\n\n\n
                                                                                                  • Absorption pattern
                                                                                                    • Prompt absorption from aqueous solution, but slow and sustained from repository preparations<\/li><\/ul><\/li>
                                                                                                    • Suitable for:
                                                                                                      • Poorly soluble suspensions and slow release implants (sc)<\/li>
                                                                                                      • Moderate volumes and some <\/em>irritating substances (im)<\/li>
                                                                                                      • Appropriate for self-administration (eg insulin<\/strong>)<\/li><\/ul><\/li>
                                                                                                      • Limitations and precautions
                                                                                                        • Not suitable for large volumes and pain and necrosis at injection sites for certain drugs (sc) eg thiopentone<\/strong><\/li>
                                                                                                        • Precluded during anticoagulant therapy (im)<\/li>
                                                                                                        • May interfere with interpretation of certain diagnostic tests (eg. creatine kinase) (im)<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                                                          <\/div>\n\n\n\n
                                                                                                          \"\"<\/figure>
                                                                                                          \n

                                                                                                          Rectal (PR)       <\/strong><\/h2>\n\n\n\n
                                                                                                          • Can be used for a local or systemic effect<\/li>
                                                                                                          • Unconscious patients, children with poor IV access, if patient is vomiting<\/li>
                                                                                                          • Easy to terminate exposure<\/li>
                                                                                                          • Absorption may be variable<\/li>
                                                                                                          • Good for drugs affecting the bowel such as laxatives \/ cathartics \/ drugs for ulcerative colitis<\/li><\/ul>\n<\/div><\/div>\n\n\n\n
                                                                                                            <\/div>\n\n\n\n
                                                                                                            \"\"<\/figure>
                                                                                                            \n

                                                                                                            Spinal\/Epidural       <\/strong><\/h2>\n\n\n\n
                                                                                                            • Into spinal\/epidural space for delivery of local anaesthetics\/opioids for pain control<\/li>
                                                                                                            • Preferred over GA in lower abdominal or lower limb surgery or in child birth<\/li><\/ul>\n\n\n\n

                                                                                                              <\/p>\n<\/div><\/div>\n\n\n\n

                                                                                                              <\/div>\n\n\n\n
                                                                                                              \"\"<\/figure>
                                                                                                              \n

                                                                                                              Topical (TOP) 1       <\/h2>\n\n\n\n
                                                                                                              • Mucosal membranes
                                                                                                                • Nasal, vaginal, etc.<\/li>
                                                                                                                • zolmitriptan <\/strong>spray \u2013 migraine<\/li><\/ul><\/li><\/ul>\n\n\n\n

                                                                                                                  <\/p>\n<\/div><\/div>\n\n\n\n

                                                                                                                  <\/div>\n\n\n\n

                                                                                                                  Topical (TOP) 2      <\/h2>\n\n\n\n
                                                                                                                  • Skin<\/strong>
                                                                                                                    • 1. dermal (local)<\/li>
                                                                                                                    • 2. transdermal (systemic)<\/li>
                                                                                                                    • Stable blood levels<\/li>
                                                                                                                    • No first pass metabolism<\/li>
                                                                                                                    • Drug must be potent and lipophilic
                                                                                                                      • scopolamine <\/strong>\u2013 motion sickness<\/li>
                                                                                                                      • oestradiol <\/strong>\u2013 hormone replacement<\/li>
                                                                                                                      • fentanyl <\/strong>\u2013 pain<\/li>
                                                                                                                      • clonidine <\/strong>\u2013 hypertension<\/li>
                                                                                                                      • nicotine <\/strong>\u2013 tobacco withdrawal<\/li>
                                                                                                                      • nitrates <\/strong>\u2013 angina<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                                                                        \"Topical<\/figure><\/div>\n","protected":false},"excerpt":{"rendered":"

                                                                                                                        Learning Objectives Understand the effect of pH partitioning and lipid solubility on drug absorption Describe factors affecting the absorption of drugs via oral administration especially first-pass metabolism Understand the suitability, limitations and precautions of various routes of administration Outline the concept of bioavailability References Rang HP, Dale MM, Ritter JM,  Flower R and Henderson G (2015) Pharmacology, […]<\/p>\n","protected":false},"author":4934,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"page-template\/generic-template.php","meta":{"_acf_changed":false,"footnotes":""},"class_list":["post-45616","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"\nPharmacokinetics 1: Administration & Absorption - UTS Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/educationexpress.uts.edu.au\/pharmacology\/pharmacokinetics-1-administration-absorption\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Pharmacokinetics 1: Administration & Absorption - 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