Biopharmaceutics lecture4(2)


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Biopharmaceutics lecture4(2)

  1. 1. Routes of Drug Administration Presented by: Marcia Williams
  2. 2. Routes of Drug Administration Introduction <ul><li>May be classified as </li></ul><ul><ul><li>ENTERAL and </li></ul></ul><ul><ul><li>PARENTERAL. </li></ul></ul><ul><li>Enteral means has to do with the GI tract and includes oral, buccal, and rectal. </li></ul><ul><li>Parenteral means not through the alimentary canal and commonly refers to injections such as IV, IM, and SC; but could also include topical and inhalation. </li></ul><ul><li>IV can be distinguished from the rest, as with all others at least one membrane must be crossed, thus an absorption process is involved in the administration and the pharmacokinetics. </li></ul>
  3. 4. Buccal/Sublingual Route <ul><li>Drug is taken as smaller tablets which are held in the mouth or under the tongue. </li></ul><ul><li>Buccal tablets are often harder tablets [4 hour disintegration time], designed to dissolve slowly. Nitroglycerin, as a softer sublingual tablet [2 min disintegration time] may be used for the rapid relief of angina. </li></ul><ul><li>This ROA is also used for some steroids such as testosterone and oxytocin. </li></ul><ul><li>Nicotine containing chewing gum may be used for cigarette smoking replacement. </li></ul>
  4. 5. Buccal/Sublingual Route <ul><li>Factors affecting oral mucosal delivery: </li></ul><ul><li>Lipophilicity of the drug: </li></ul><ul><ul><li>Slightly higher lipid solubility required than for GI absorption </li></ul></ul><ul><li>Salivary secretion : </li></ul><ul><ul><li>Absorption is delayed if mouth is dry </li></ul></ul><ul><ul><li>Drug must be soluble in aqueous buccal fluid. </li></ul></ul><ul><li>pH of the saliva </li></ul><ul><ul><li>Usually around 5 </li></ul></ul><ul><ul><li>Favourable absorption rate for unionized drug </li></ul></ul>
  5. 6. Factors affecting oral mucosal delivery (cont’d) <ul><li>Binding to oral mucosa </li></ul><ul><ul><li>Binding decreases bioavailability </li></ul></ul><ul><li>Thickness of oral epithelium </li></ul><ul><ul><li>Sublingual faster than buccal </li></ul></ul>
  6. 7. Advantages of buccal sublingual administration <ul><li>First pass - The liver is by-passed thus there is no loss of drug by first pass effect for buccal administration. Bioavailability thus is higher. </li></ul><ul><li>Rapid absorption - Because of the good blood supply to the area absorption is usually quite rapid. </li></ul><ul><li>Drug stability - pH in mouth relatively neutral (cf. stomach - acidic). Thus a drug may be more stable. </li></ul>
  7. 8. Disadvantages of buccal sublingual administration <ul><li>Holding the dose in the mouth may be inconvenient. </li></ul><ul><li>If any is swallowed that portion must be treated as an oral dose and subject to first pass metabolism. </li></ul><ul><li>Only small doses can be accommodated easily. </li></ul>
  8. 9. Isosorbide concentrations after a 5 mg oral or sublingual dose. Data from: Assinder et al. J Pharm Sci 66:775, 1977.
  9. 10. Effect of buffer pH on the buccal absorption of nicotine Adapted from: Svensson CK. Clin Pharmacokinet 12:30, 1987.
  10. 11. Rectal Route of Administration <ul><li>Most commonly used for suppository or enema. </li></ul><ul><li>Some drugs given by this route include: </li></ul><ul><ul><li>aspirin, dipyrone, paracetamol, theophylline, chlorpromazine and some barbiturates </li></ul></ul><ul><li>Advantages: </li></ul><ul><li>By-pass liver - Some of the veins draining the rectum lead directly to general circulation - by-passing the liver. </li></ul><ul><li>Useful for patients unable to take drugs orally or with younger children. </li></ul><ul><li>Disadvantages: </li></ul><ul><li>Erratic absorption - incomplete and erratic. </li></ul><ul><li>Not well accepted. </li></ul>
  11. 12. Availability (%) of lidocaine after IV, oral and rectal administration Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979. Subject IV 1 100 2 100 3 100 4 100 5 100 6 100 100 Oral 17 49 53 13 35 37 34 Rectal 59 87 80 31 100 59 71
  12. 13. Intravenous Route of Administration <ul><li>Drugs may be given into a peripheral vein over 1 to 2 minutes or longer by infusion. </li></ul><ul><li>Rapid injections are used to treat epileptic seizures, acute asthma, or cardiac arrhythmias etc. </li></ul>
  13. 14. Intravenous Route of Administration <ul><li>Advantages: </li></ul><ul><li>Rapid - A quick response is possible </li></ul><ul><li>Total dose - The whole dose is delivered to the blood stream. Large doses can be given by extending the time of infusion. </li></ul><ul><li>Veins relatively insensitive - to irritation by irritant drugs at high concentration in dosage forms. </li></ul>
  14. 15. Intravenous Route of Administration <ul><li>Disadvantages: </li></ul><ul><li>It may be difficult to find a suitable vein. </li></ul><ul><li>May be toxic - Because of the rapid response, toxicity can be a problem with rapid drug administrations, could then be given as an infusion while monitoring for toxicity. </li></ul><ul><li>Requires trained personnel - Trained personnel are required to give intravenous injections. </li></ul><ul><li>Expensive - Sterility, pyrogen testing and larger volume of solvent means greater cost for preparation, transport and storage. </li></ul><ul><li>Risk of infection. </li></ul>
  15. 16. Intravenous Route of Administration <ul><li>There are some preparations that, due to poor solubility of the drug, contain solvents that may produce rate-related toxicity. For example, diazepam injection USP contains 40% propylene glycol, among other solvents. Injected rapidly, diazepam may induce hypotension or arrhythmias. For this reason, it is recommended that IV injections of diazepam be given no more rapidly than 1 mL/min. </li></ul>
  16. 17. While it is generally viewed that 100% of drug administered intravenously is bioavailable, prodrug administration via this route may result in less than 100% bioavailability . Drug Bioavailability Chloramphenicol succinate ~70% Dexamethasone phosphate ~90% Dexamethasone sulfate ~40% Prednisolone phosphate ~90% Prednisolone phthalate ~50% Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitate IV PO Mean C90-min (mg/L) 22.6 27.5 Mean AUC (mg/hr/L) 78 110
  17. 18. Subcutaneous Route of Administration <ul><li>This involves administration of the drug dose just under the skin. </li></ul><ul><li>Advantages: </li></ul><ul><li>Can be given by patient, e.g. in the case of insulin </li></ul><ul><li>Absorption slow but usually complete. Absorption rate can be improved by massage or heat. </li></ul><ul><li>Vasoconstrictor may be added to reduce the absorption of a local anesthetic agent, thereby prolonging its effect at the site of interest. </li></ul>
  18. 19. Subcutaneous Route of Administration <ul><li>Disadvantages: </li></ul><ul><li>Can be painful </li></ul><ul><li>Irritant drugs can cause local tissue damage </li></ul><ul><li>Maximum of 2 ml injection thus often small doses limit use. </li></ul>
  19. 20. D. Subcutaneous Advantages: <ul><li>prompt absorption from aqueous solns </li></ul><ul><li>little training necessary </li></ul><ul><li>avoid harsh GI tract environment </li></ul><ul><li>can be used for suspensions </li></ul>Disadvantages: <ul><li>cannot be used for large volumes </li></ul><ul><li>potential pain and tissue damage </li></ul><ul><li>variability in absorption from various sites </li></ul>
  20. 21. Subcutaneous Route of Administration <ul><li>Methods of increasing the rate of absorption </li></ul><ul><li>Enhancing blood flow to the site of injection </li></ul><ul><ul><li>By massaging, application of heat, co-administration of vasodilators locally or by exercise. </li></ul></ul><ul><li>Increasing the drug-tissue contact area: </li></ul><ul><ul><li>By co-administering the enzyme hyaluronidase that breaks down the connective tissue - permits the drug to spread </li></ul></ul>
  21. 22. Subcutaneous Route of Administration <ul><li>Methods of decreasing the rate of absorption </li></ul><ul><li>Vasoconstriction </li></ul><ul><ul><li>By local cooling </li></ul></ul><ul><ul><li>Co-injection of a vasoconstrictor such as adrenaline </li></ul></ul><ul><ul><li>Immobilization of limb </li></ul></ul>
  22. 23. Sites for SC injection
  23. 24. Disappearance of I 125 -insulin from subcutaneous injection at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980 .
  24. 25. Disappearance of I 125 -insulin from subcutaneous injection at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.
  25. 26. Intramuscular Route of Administration <ul><li>Intramuscular </li></ul><ul><li>Injection is administered into the gluteal muscle of the buttock or the deltoid muscle of the upper arm and the vastus lateralis muscle of the thigh. </li></ul><ul><li>Larger volume than SC can be given by IM </li></ul><ul><li>A depot or sustained release effect is possible with IM injections, e.g. procaine penicillin </li></ul><ul><li>The site of injection will influence the absorption, generally the deltoid muscle is the best site </li></ul><ul><li>Absorption is sometimes erratic, especially for poorly soluble drugs, e.g. diazepam, phenytoin. </li></ul><ul><li>The solvent may be absorbed faster than the drug causing precipitation of the drug at the site of injection. </li></ul>
  26. 27. Advantages: <ul><li>less skill necessary for administration </li></ul><ul><li>can be used to administer oily vehicles </li></ul><ul><li>prompt absorption from aqueous sol’n </li></ul>Disadvantages: <ul><li>painful </li></ul><ul><li>cannot be used in presence of abnormal clotting time </li></ul><ul><li>drug may ppt at the site of administration </li></ul><ul><li>variability in bioavailability </li></ul>Z-track method for IM injections
  27. 28. Injection site deltoid vastus lateralis gluteus maximus Males 11.7 9.8 11.1 Females 10.2 9.4 4.3 Data from: Vukovich et al. Clin Pharmacol Ther 18:215, 1975. Peak plasma cephradine concentrations (mcg/mL) after IM administration to different sites in male and female subjects
  28. 29. Inhalation Route of Administration <ul><li>Drugs administered as fine particles of liquids or solids or as aerosols or spray. The drug may be required for local or systemic effects. </li></ul><ul><li>Local effect - bronchodilators </li></ul><ul><li>Systemic effect - general anesthesia </li></ul><ul><li>Rapid absorption, by-passing the liver </li></ul><ul><li>Absorption of gases is relatively efficient, </li></ul><ul><li>Solids and liquids are excluded if larger than 20 micron and even then only 10 % of the dose may be absorbed. </li></ul><ul><li>Cromolyn is taken as a powder with 50 % of the particles within the range of 2 to 6 micron. If particles are larger than 20 micron they will impact on the mouth and throat and if smaller than 0.5 micron, they will not be retained. </li></ul>
  29. 30. C. Nasal <ul><li>Historically utilized only for local effects </li></ul><ul><li>Growing number of compounds administered intranasally that are intended for systemic effects </li></ul><ul><li>For drugs that are destroyed in the GI environment (or first-pass effect) </li></ul><ul><li>As an alternative to intravenous administration – better safety and patient acceptance </li></ul>Drugs include anticonvulsants (midazolam), narcotic antagonists (naloxone), peptides (calcitonin, insulin), and smoking cessation agents (nicotine)
  30. 31. Mucosal Atomizer Device From: Intranasal naloxone administration in the field by paramedics
  31. 32. Factors that influence absorption from the nasal mucosa <ul><li>pH </li></ul><ul><li>Concentration </li></ul><ul><li>Molecular weight </li></ul><ul><li>Formulation </li></ul><ul><li>Condition of nasal mucosa </li></ul>
  32. 33. Figure from: Nasal to brain delivery of drugs
  33. 34. Topical Route of Administration <ul><li>Local effect - eye drops, antiseptic, sunscreen, callous removal, etc. </li></ul><ul><li>Systemic effect - e.g., nitroglycerin ointment. </li></ul><ul><li>Absorption through the skin, especially via cuts and abrasions but also intact, can be quite marked. This can be a real problem in handling toxic materials in the laboratory or pharmacy. </li></ul>
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