Pharmacokinetics

• First Pass Effect

  • "First Pass Metabolism"

    Saffarzadeh A First Pass Metabolism - Pharmacology Lect 6. https://www.youtube.com/watch?v=5AB8WkCbz4k . Areo Saffarzadeh excellent home site:  https://www.youtube.com/user/areosaf .

  • First-pass Elimination:

    • Transport sequence:

      • Across the gut wall into the portal circulation.

      • Portal blood transports of the drug to the liver.

      • The drug may then reach the systemic circulation.

    1. Drug bioavailability may be affected by the above steps

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

      • Drug metabolism (potentially extensive) may occur in liver

        • The liver may excrete drug into the bile

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

     

  • 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)

    • Drugs poorly extracted by the liver

      • Phenytoin (Dilantin)

      • Diazepam (Valium)

      • Digitoxin (Crystodigin)

      • Chlorpropamide (Dibese)

      • Theophylline

      • Tolbutamide (Orinase)

      • Wafarin (Coumadin)

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

  • Pulmonary Implications: Pharmacokinetics

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

  •  

    First pass pulmonary uptake > 65% of dose

    Lidocaine (Xylocaine)	Propranolol (Inderal)	Meperidine (Demerol)
    Fentanyl (Sublimaze)	Sufentanil (Sufenta)	Alfentanil (Alfenta)

  • 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

  • Volume of Distribution

    Volume of distribution (V_d) is the ratio between the amount of drug in body (dose given) and the concentration of the drug (C) measured in blood or plasma.

    • V_d = (amount of drug in body)/C where C is the concentration of drug in blood or plasma.

    • V_d as calculated is an apparent volume of distribution. For example:

      • V_d for digoxin is 440 L/70 kg (liters per 70 kg person)

      • V_d for chloroquine is 13,000 L/70 kg (liters per 70 kg person)

      • Such very large V_d would be consistent with very high tissue binding, leaving little free in plasma or blood

    • V_d is an apparent volume of distribution, since V_d is the volume needed to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or plasma water.

      • Many drugs have a much higher concentration in extravascular compartments (therefore these drugs are NOT homogeneously distributed)

    •   Physical volumes (L./kg body weight) for some body compartments

      • Water

        • Total Body Water (0.5-0.7 L/kg) or about 35000 to 49000 ml (70 kg individual)

        • Extracellular Water (0.2 L./kg)

        • Blood (0.08 L./kg);

        • Plasma (0.04 L./kg)

      • Fat

        • 0.2 - 0.35 L./kg 

      • Bone

        • 0.07 L/kg

  • Factors influencing the volume of distribution

    • Drug pK_a

    • Extent of drug-plasma protein binding

    • Partition coefficient of the drug in fat (lipid solubility)

    • V_d may be affected by:

      • Patient's gender

      • Patient's age

      • Patient's disease

      • Patient's body composition

      • Example of a poorly lipid soluble agent with a V_d about equal to extracellular fluid volume: Nondepolarizing neuromuscular blocking drugs.

  References

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