Strath Parenteral 2009 Annotated

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3rd Year lecture material B.Pharm. course

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Strath Parenteral 2009 Annotated

  1. 1. Parenteral Delivery Strathclyde 2009 annotated
  2. 2. Parenteral Delivery <ul><li>Different administration routes, that generally involve the use of a hypodermic needle to inject the drug into the body. </li></ul>
  3. 3. Original syringe from 1856, Royal College of Surgeons, Edinbourgh, Scotland <ul><li>In these times, hypodermic syringes were mainly used to deliver tincture of morphine. The alcohol (usually as sugary drink called Sherry) was used as the drug solvent </li></ul>
  4. 4. Parenteral Routes <ul><ul><li>Intravenous </li></ul></ul><ul><ul><li>Intralymphatic </li></ul></ul><ul><ul><li>Subcutaneous </li></ul></ul><ul><ul><li>Intramuscular </li></ul></ul><ul><ul><li>Intralipomatous </li></ul></ul><ul><ul><li>Epidural </li></ul></ul><ul><ul><li>Spinal (intrathecal) </li></ul></ul><ul><ul><li>Microdialysis </li></ul></ul>
  5. 5. Avoiding First Pass effect Heart Gut lumen Liver Circulation i.v. i.m. s.c. Buccal Pulmonary In oral delivery, veins from the gut pass first through the Liver (hepatic portal system). Buccal & Pulmonary avoid this barrier
  6. 6. Parenteral Delivery <ul><li>bypasses a number of physiological barriers. </li></ul><ul><li>U s u ally employed for the rapid attainment of a pharmacological effect or when the drug is too hydrophilic to cross the gastrointestinal tract </li></ul><ul><li>Rapid onset of action: titratable effects, especially continuous i.v infusion. </li></ul><ul><li>Increased hazards due to immediacy of action therefore requires therapeutic supervision. </li></ul><ul><li>Attempts to simplify regimen by depot formulation development </li></ul>
  7. 7. Small Volume Injectables: immediate formulations <ul><li>Ready to use : </li></ul><ul><ul><li>Aqueous solutions </li></ul></ul><ul><ul><li>Non-aqueous solutions – propylene glycol, ethanol, oils </li></ul></ul><ul><li>Lyophilised preparations to be reconstituted </li></ul><ul><li>Suspensions </li></ul><ul><li>Emulsions </li></ul>
  8. 8. Small Volume Injectables: depot formulations <ul><li>Use of viscous water-miscible formulations. </li></ul><ul><li>Use of water-immiscible vehicles = vegetable oils </li></ul><ul><li>Formulation of thixotropic suspensions </li></ul><ul><li>Formation of water insoluble salts, complexes and esters </li></ul><ul><li>Dispersion in polymeric microspheres or microcapsules </li></ul><ul><li>Coadministration of vasoconstrictors </li></ul><ul><li>Propylene glycol etc </li></ul><ul><li>Penicillin procaine-G in vegetable oil gelled with aluminium monostearate </li></ul><ul><li>Penicillin G procaine 4 mg ml cf Pen G benzathine 0.2 mg ml </li></ul><ul><li>Local anaesthetics eg lidocaine </li></ul>
  9. 9. Effect of particle size: penicillin G procaine i.m (Buckwater & Dickison, 1958). 300,000 unit/ml administered to rabbits Serum Conc. (units/ml)
  10. 10. Effect of aluminium monostearate in penicillin G procaine suspension . Rabbits 300, 000 units per ml. After Buckwater & Dickison 1958 m.i.c. 0.03 units /ml Serum Conc. (units/ml) 0 1 2 3 4 5 6 7 Days
  11. 11. The body <ul><li>The overall body composition is made up (approximately!) as follows: </li></ul><ul><li>Water 60%. </li></ul><ul><li>protein 18%. </li></ul><ul><li>15% fat. </li></ul><ul><li>minerals 7 %. </li></ul>
  12. 12. Water in the body <ul><li>The compartments available to the drug when in the body are a determinant of the starting concentration </li></ul><ul><li>As an example, think of the difference between a drug trapped in plasma (3 litres) versus that which easily moves into extracellular fluid (15 litres) </li></ul>0 20 40 60 80 T.B.W I.C.F. E.C.F. Plasma Volume Blood Volume
  13. 13. Body water <ul><li>Of the Body Water </li></ul><ul><ul><li>40% is intercellular fluid </li></ul></ul><ul><ul><li>20% is extracellular fluid </li></ul></ul><ul><li>E.C.F. comprises </li></ul><ul><ul><li>interstitial fluid 15% and plasma 5% </li></ul></ul><ul><li>The total blood volume is 8% Body Water, with 3% associated with red cells being part of the intercellular fluid volume. </li></ul>
  14. 14. Infant – 75% water
  15. 15. Adult 60% water <ul><li>If a person is excessively fat or thin, then dosing on a mg/kg basis will have inbuilt errors resulting in differences in concentrations </li></ul>Ectomorph Mesomorph or Endomorph ?
  16. 16. The Elderly - 45% water
  17. 17. Drug Movement
  18. 18. Concentration of drug at site of action and persistence of drug in the body <ul><li>Depends on: </li></ul><ul><li>Frequency of dose; Formulation </li></ul><ul><li>Rate and extent of absorption </li></ul><ul><li>Rate and extent of distribution </li></ul><ul><ul><li>Blood  tissues </li></ul></ul><ul><li>Rate of excretion </li></ul><ul><li>Rate of metabolism </li></ul>Biopharm 1-II -1 ELIMINATION Wood rate of Eqm 2
  19. 19. The Importance of a blood supply...
  20. 20. This video illustrates movement of material from large vessels to the Capillary bed
  21. 21. Parenteral Delivery <ul><li>In most cases, the rate that the drug in the plasma compartment achieves an equilibrium with other tissues as a function of blood flow. </li></ul>
  22. 22. Blood Flow <ul><li>Blood 5.4 8.0 </li></ul><ul><li>Rapidly Perfused </li></ul><ul><li>Brain 0.75 2.0 </li></ul><ul><li>Liver 1.55 3.5 </li></ul><ul><li>Kidney 1.2 0.5 </li></ul><ul><li>Less rapidly perfused </li></ul><ul><li>Muscle 0.8 48 </li></ul><ul><li>Skin 0.4 6.5 </li></ul><ul><li>Poorly perfused </li></ul><ul><li>Fat 0.25 14 </li></ul><ul><li>Skeletom 0.2 17 </li></ul>Blood flow Tissue Mass (Litres/min) (% Total body weight )
  23. 23. Other vascular issues Day 1 Day 5
  24. 24. Tissue necrosis Day 10 Brown Recluse Spider (Colorado)
  25. 25. Disorders of venous return <ul><li>Venous stasis ulcers, common in the elderly </li></ul><ul><li>May be associated with congestive heart failure following kidneys disease (swollen ankles) </li></ul><ul><li>or Deep Vein Thrombosis or superficial phlebitis </li></ul>
  26. 26. <ul><li>Q /VT Time to equilibrium </li></ul><ul><li>(blood flow per g tissue) (min) </li></ul><ul><li>Kidney 4.0 0.25 </li></ul><ul><li>Muscle 0.025 40 </li></ul><ul><li>Adipose 0.03 4000 </li></ul><ul><li>Adipose tissue is more peripheral than muscle tissue (further away from arterial supply) </li></ul>Flow per g tissue and Equilibrium
  27. 27. Drug Plasma Concentration-Time Profile
  28. 28. Distribution <ul><li>Drugs distribute unevenly between red cells, white cells, plasma protein and plasma water. Once in the blood, a drug diffuses throughout the various body fluid compartments at rates and to extents dependent on its chemical characteristics. </li></ul>
  29. 29. Capillary Permeability <ul><li>Cells overlap at margins - in some places barrier is only one cell thick (e.G. Blood capillaries) </li></ul><ul><li>In the liver, the smallest channels of the circulation - SINUSOIDS - lack even an endothelium </li></ul>
  30. 30. Capillary Permeability: Lipid soluble molecules <ul><li>Lipid solubility and surface area remains important characteristic determining absorption rate </li></ul>
  31. 31. Capillary Permeability: Water soluble molecules <ul><li>SMALL water soluble molecules cross at rates directly proportional to their concentration gradients and as if they were diffusing in water </li></ul><ul><li>LARGE water soluble species influenced by hydrostatic pressure gradient (arterial-venous difference in the capillary bed) </li></ul><ul><li>The ease in crossing endothelium is due to the high surface area - blood capillaries present a barrier only to macromolecules </li></ul>
  32. 32. <ul><li>. Low blood flow: Perfusion limits distribution rate, protein binding has no effect, dissociation of protein/drug complex is very rapid. </li></ul>Effect of protein Binding on Distribution Rate Drug has plenty of time to equilibrate
  33. 33. Effect of protein Binding on Distribution Rate <ul><li>.High blood flow : When diffusion limits distribution rate, protein binding may slow down distribution because it reduces concentration gradient. </li></ul>Blood passed the delivery site very quickly therefore protein binding is important – wouldn’t see this in peripheral tissue because blood flow slower
  34. 34. The Plasma Concentration - Time profile <ul><li>Many drugs show mono-exponential clearance, indicating distribution is rapid </li></ul><ul><li>Drugs showing biexponential clearance are undergoing a slow equilibration </li></ul>10 0 0 1 2 3 4
  35. 35. Volume of distribution 10 1 0.1 3 600 mg dose At T 0 , Ct 0 = 3 ug/ml 0 1 2 3 4 Vd = 600/3 = 200 litres If weplot the data on a log axis and extrapolate back to zero, we can estimate the size of the compartment we are draining from
  36. 36. Body fat Less VD than predicted for Water soluble drugs: Higher Concentration
  37. 37. Body fat More VD than predicted for Lipid soluble drugs: Lower Concentration & slow equilibrium
  38. 38. Injection causes damage
  39. 39. Tissue reaction after subcutaneous injection of a suspension of insulin crystals Areas of collagen bands and vacuolated tissue
  40. 40. Foreign body reaction <ul><li>Ingrowing hairs in the neck are causing a foreign body reaction in the subcutaneous tissue </li></ul>
  41. 41. Foreign body reaction <ul><li>Reaction to silicone escape from a breast implant. </li></ul><ul><li>Note the fusion of phagocytes to form a giant cell that is attempting to reduce the lesion </li></ul>
  42. 42. Muscle damage after intramuscular injection Necrotic muscle tissue Scarring occurs on the inside as well
  43. 43. Tissue damage after intramuscular or intralipomateous injection in pigs <ul><li>Compare the spread of the injection when digoxin is injected into adipose tissue (Left) or muscle (Right) </li></ul>Intralipomateous Intramuscular
  44. 44. Injection into buttocks (MRI guided) Treating an area around the pelvis Local to numb pain
  45. 45. Thickness of subcutaneous fat layer in man at injection site <ul><li>About 5 cm in man, 7 cm in women </li></ul>Men are more prone to injection site damage than women because of the gender effect on fat distribution
  46. 46. Parenteral Delivery <ul><li>Injection into fat slows the rate of distribution and the poor perfusion results in a poor inflammatory response </li></ul><ul><li>Muscle is well perfused, often injured and responds quickly to insult </li></ul><ul><li>Women have more subcutaneous fat than men, therefore….! </li></ul>
  47. 47. Parenteral Delivery Unabsorbed drug In solution Membrane Membrane Bound Plasma & ECF ICF Storage Sites Receptors Only unbound, unionised drug can cross membrane Ionised Non Ionised Ionised Non Ionised Ionised Non Ionised
  48. 48. Thiopentone kinetics <ul><li>Note biexponential clearance from plasma </li></ul><ul><li>Note steady build up in fat </li></ul>
  49. 49. REDISTRIBUTION
  50. 50. i.m. Injection of [ 131 I] NaI
  51. 51. [I-131] iodide kinetics 0.1h <ul><li>General distribution </li></ul><ul><li>Colour scale represents activity red>yellow>green> blue </li></ul>
  52. 52. [I-131] iodide kinetics 1.8h <ul><li>Accumulation in Salivary glands/thyroid glands ; stomach and elimination by kidneys (bladder image) </li></ul>
  53. 53. [I-131] iodide kinetics 5.6h <ul><li>Salivary glands cleared; activity remains in thyroid and stomach </li></ul><ul><li>Bladder image still prominent </li></ul>
  54. 54. [I-131] iodide kinetics 7 days <ul><li>Just the thyroid image remains </li></ul>
  55. 55. [I-131] iodide kinetics <ul><li>Attempt to quantify loss from injection site (1) </li></ul><ul><li>Label will be carried away by the body in the blood stream and will redistribute over the top of the region of interest </li></ul><ul><li>To get true count, draw ROI over contralateral limb (2) and subtract from (1) </li></ul>
  56. 56. i.m. kinetics <ul><li>Log y axis </li></ul><ul><li>Shows biphasic fall in counts (1) </li></ul><ul><li>Rise in activity, contralateral limb (2) </li></ul><ul><li>True loss (2-1) </li></ul>1 2 1-2
  57. 57. Thiopentone kinetics <ul><li>The slow distribution and feed from the adipose tisssue controls the rate at which all the other body compartments clear </li></ul>
  58. 58. Guanethidine kinetics Plasma Liver Kidney Skeletal muscle Heart muscle Distribution following i.v. administration In this case the drug has been accumulated in a tissue by an active process. Guanethidine accumulates in synaptic vesicles at the neuromuscular junction
  59. 59. Hazards of parenteral delivery <ul><li>Risk of infection </li></ul><ul><li>Risk of pyrogenicity </li></ul><ul><li>Risk of anaphylactic shock </li></ul><ul><li>Cannot reverse delivery </li></ul><ul><li>Fast onset of action </li></ul><ul><li>Problems with the obese, the elderly and the very young </li></ul>
  60. 60. Issues <ul><li>Sterility </li></ul><ul><li>Freedom from pyrogens </li></ul><ul><li>Freedom from particulates </li></ul><ul><li>Stability </li></ul>

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