Oral Administration

• Most convenient, most economical

•  Disadvantages:

  • emesis (drug irritation of the gastrointestinal mucosa)

  • digestive enzymes/gastric acidity destroys the drug

  • unreliable or inconsistent absorption due to food or other drug effects

  • metabolism of the drug by gastrointestinal flora

• Factors determining rate of drug effect onset

  • Primary factor:

    • Rate & absorption extent by GI tract

  • Absorption Site:

    • mainly small intestine because of large surface area

  • Drug ionization state:

    • nonionized (lipid-soluble) forms favor absorption

      • weak acids may be highly ionized in the alkaline intestinal pH (not favoring absorption) but this effect is counterbalanced by the large surface-area effect

      • drugs which are weak acids are readily absorbed in the stomach

• First-Pass Effect

  • Drugs absorbed from the GI tract passes through the portal venous system then through the liver and finally into the systemic circulation when drugs interact with receptors in target tissues.

  • Extensive hepatic metabolism/extraction result in minimal drug delivery to the systemic circulation for certain agents.

  • Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration

    • Examples:

      • propranolol

      • lidocaine

Transdermal Administration

• Advantages:

  • sustained, therapeutic plasma levels (reduced peaks/valleys associated with intermittent drug administrations)

  • Avoids continuous infusion technique difficulties

  • Low side effect incidence (smaller doses)

  • Generally good patient compliance

• Factors contributing to reliable transdermal drug absorption:

  • molecular weight < 1000

  • pH range 5-9 in aqueous medium

  • no histamine-releasing action

  • daily drug requirement <10 mg

• Example of drugs available for transdermal delivery:

  • scopolamine:-tolerance may eventually occur; resulting in loss of therapeutic action

  • fentanyl (Sublimaze)

  • clonidine (Catapres)

  • nitroglycerin-tolerance may eventually occur; resulting in loss of therapeutic action

• Proximal rectum administration: Absorption into superior hemorrhoidal veins then enters the portal venous system  then to the liver (possible first pass hepatic effect) and finally into the systemic circulation

• Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver

• Generally unpredictable pharmacological responses for the above reasons

• Rectal mucosal irritation possible

• Ensures active drug absorption

• subcutaneously intramuscular injection: more rapid/predictable than oral administration route

• only route of administration acceptable for:

  • uncooperative patients

  • unconscious patients

• Factors the determine rate of systemic absorption:

  • absorbing capillary membrane surface area

  • drug solubility in interstitial fluid

  • aqueous channels (vascular endothelium) promote high diffusion rates of drugs, independent of their lipid solubility

• Advantages of IV administration

  • rapid/precise blood drug levels obtained (e.g., no first-pass effect)

  • Irritant drugs: more comfortably administered (blood vessels relatively insensitive); drug rapidly diluted (particularly if administered into large forearm vein)

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

First-pass Elimination

• Transport sequence:

  1. across the gut wall into the portal circulation

  2. portal blood transports of the drug to the liver

  3. the drug may then reach the systemic circulation

  4. bioavailability may be affected by steps 1 -- 3

• drug metabolism may occur in the intestinal wall or in the blood

• drug metabolism (potentially extensive) may occur in liver

•  liver may excrete drug into the bile

•  overall process that contributes to bioavailability reduction is the first-pass lost or elimination

• Magnitude of first pass hepatic effect: Extraction ratio (ER)

  • ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour {1500 ml/min})

  • Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):

    • F = f x (1 -ER)

Extraction Ratios, Routes of Administration, and the First-Pass Effect

• Some drugs that exhibit high extraction by the liver are given orally. 

  • Some examples -- desipramine (Norpramin), imipramine (Tofranil), meperidine (Demerol), propranolol (Inderal), amitriptyline (Elavil, Endep), isoniazid (INH).

• Some drugs which have relatively low bioavailability are not given orally because of concern of metabolite toxicity -- lidocaine is an example (CNS toxicity, convulsions)

• High extraction ratio drugs show interpatient bioavailability variation because all of sensitivity to:

  • hepatic function

  • blood flow

  • hepatic disease (intrahepatic or extrahepatic circulatory shunting)

• Avoiding the first-pass effect:

  • sublingual (e.g. nitroglycerin)-- direct access to systemic circulation

  • transdermal

  • use of suppositories in the lower rectum {if suppositories move upward, absorption may occur through the superior hemorrhoidal veins, which lead to the liver}

  • inhalation: although first-pass pulmonary loss by excretion or metabolism may occur.

• Important for uptake of injected/intravenously administered drugs -- particularly lipophilic amines (pKa= 8)

• Pulmonary uptake:

  • Effects peak arterial concentration

  • May serve as a reservoir, enabling transport of drug into systemic circulation

• First-pass pulmonary effect magnitude not affected by:

  • spontaneous respiration

  • controlled ventilation

  • apnea

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.