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Biopharmaceutics lecture4

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Text of Biopharmaceutics lecture4

  • Routes of Drug Administration

    Presented by:

    Marcia Williams

  • Routes of Drug Administration Introduction

    May be classified as

    ENTERAL and

    PARENTERAL.

    Enteral means has to do with the GI tract and includes oral, buccal, and rectal. 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. 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.
  • Buccal/Sublingual
    Route

    Drug is taken as smaller tablets which are held in the mouth or under the tongue.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. This ROA is also used for some steroids such as testosterone and oxytocin. Nicotine containing chewing gum may be used for cigarette smoking replacement.
  • Buccal/Sublingual
    Route

    Factors affecting oral mucosal delivery:

    Lipophilicity of the drug:

    Slightly higher lipid solubility required than for GI absorption

    Salivary secretion:

    Absorption is delayed if mouth is dry

    Drug must be soluble in aqueous buccal fluid.

    pH of the saliva

    Usually around 5

    Favourable absorption rate for unionized drug

  • Factors affecting oral mucosal delivery (contd)

    Binding to oral mucosa

    Binding decreases bioavailability

    Thickness of oral epithelium

    Sublingual faster than buccal

  • Advantages of buccal sublingual administration

    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. Rapid absorption - Because of the good blood supply to the area absorption is usually quite rapid. Drug stability - pH in mouth relatively neutral (cf. stomach - acidic). Thus a drug may be more stable.
  • Disadvantages of buccal sublingual administration

    Holding the dose in the mouth may be inconvenient. If any is swallowed that portion must be treated as an oral dose and subject to first pass metabolism. Only small doses can be accommodated easily.
  • Isosorbide concentrations after a 5 mg oral or sublingual dose.

    Data from: Assinder et al. J Pharm Sci 66:775, 1977.

  • Effect of buffer pH on the buccal absorption of nicotine

    Adapted from: Svensson CK. Clin Pharmacokinet 12:30, 1987.

  • Rectal Route of Administration

    Most commonly used for suppository or enema. Some drugs given by this route include:

    aspirin, dipyrone, paracetamol, theophylline, chlorpromazine and some barbiturates

    Advantages: By-pass liver - Some of the veins draining the rectum lead directly to general circulation - by-passing the liver. Useful for patients unable to take drugs orally or with younger children. Disadvantages: Erratic absorption - incomplete and erratic. Not well accepted.
  • Availability (%) of lidocaine after IV, oral and rectal administration

    Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979.

    SubjectIV

    1100

    2100

    3100

    4100

    5100

    6100

    100

    Oral

    17

    49

    53

    13

    35

    37

    34

    Rectal

    59

    87

    80

    31

    100

    59

    71

  • Intravenous
    Route of Administration

    Drugs may be given into a peripheral vein over 1 to 2 minutes or longer by infusion. Rapid injections are used to treat epileptic seizures, acute asthma, or cardiac arrhythmias etc.
  • Intravenous
    Route of Administration

    Advantages:

    Rapid - A quick response is possible Total dose - The whole dose is delivered to the blood stream. Large doses can be given by extending the time of infusion. Veins relatively insensitive - to irritation by irritant drugs at high concentration in dosage forms.
  • Intravenous
    Route of Administration

    Disadvantages:

    It may be difficult to find a suitable vein. 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. Requires trained personnel - Trained personnel are required to give intravenous injections. Expensive - Sterility, pyrogen testing and larger volume of solvent means greater cost for preparation, transport and storage. Risk of infection.
  • Intravenous
    Route of Administration

    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.


  • 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)22.627.5

    Mean AUC (mg/hr/L) 78110

  • Subcutaneous Route of Administration

    This involves administration of the drug dose just under the skin.

    Advantages:

    Can be given by patient, e.g. in the case of insulin Absorption slow but usually complete. Absorption rate can be improved by massage or heat. Vasoconstrictor may be added to reduce the absorption of a local anesthetic agent, thereby prolonging its effect at the site of interest.
  • Subcutaneous Route of Administration

    Disadvantages:

    Can be painful Irritant drugs can cause local tissue damage Maximum of 2 ml injection thus often small doses limit use.
  • D. Subcutaneous

    Advantages:

    prompt absorption from aqueous solnslittle training necessaryavoid harsh GI tract environmentcan be used for suspensions

    Disadvantages:

    cannot be used for large volumespotential pain and tissue damagevariability in absorption from various sites
  • Subcutaneous Route of Administration

    Methods of increasing the rate of absorption

    Enhancing blood flow to the site of injection

    By massaging, application of heat, co-administration of vasodilators locally or by exercise.

    Increasing the drug-tissue contact area:

    By co-administering the enzyme hyaluronidase that breaks down the connective tissue - permits the drug to spread

  • Subcutaneous Route of Administration

    Methods of decreasing the rate of absorption

    Vasoconstriction

    By local cooling

    Co-injection of a vasoconstrictor such as adrenaline

    Immobilization of limb

  • Sites for SC injection

  • Disappearance of I125-insulin from subcutaneous injection

    at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.

  • Disappearance of I125-insulin from subcutaneous injection

    at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.

  • Intramuscular Route of Administration

    Intramuscular

    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.Larger volume than SC can be given by IM A depot or sustained release effect is possible with IM injections, e.g. procaine penicillin The site of injection will influence the absorption, generally the deltoid muscle is the best site Absorption is sometimes erratic, especially for poorly soluble drugs, e.g. diazepam, phenytoin. The solvent may be absorbed faster than the drug causing precipitation of the drug at the site of injection.
  • Advantages:

    less skill necessary for administrationcan be used to administer oily vehiclesprompt absorption from aqueous soln

    Disadvantages:

    painfulcannot be used in presence of abnormal clotting timedrug may ppt at the site of administrationvariability in bioavailability

    Z-track method for IM injections

  • 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

  • Inhalation
    Route of Administration

    Drugs administered as fine particles of liquids or solids or as aerosols or spray. The drug may be required for local or systemic effects.Local effect - bronchodilators Systemic effect - general anesthesia Rapid absorption, by-passing the liver Absorption of gases is relatively efficient, Solids and liquids are excluded if larger than 20 micron and even then only 10 % of the dose may be absorbed. 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.
  • C. Nasal

    Historically utilized only for local effectsGrowing number of compounds administered intranasally that are intended for systemic effe

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