First pass metabolism

INTRODUCTION:
  • A process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via the portal vein to the liver, where it is metabolized.
  • As a result, in some cases only a small proportion of the active drug reaches the systemic circulation and its intended target tissue.
  • First-pass metabolism can be bypassed by giving the drug via sublingual e.g. Isosorbide mononitrate or buccal routes.
  • The first-pass effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.
  • It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall.
DRUGS EXPERIENCING FIRST PASS METABOLISM:
  • Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.
MECHANISM OF FIRST PASS METABOLISM:
  • After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system.
  • It is carried through the portal vein into the liver before it reaches the rest of the body.
  • The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system.
  • This first pass through the liver thus greatly reduces the bioavailability of the drug.
  • The four primary systems that affect the first pass effect of a drug are the enzymes of
  1. Gastrointestinal lumen
  2. Gut wall enzymes
  3. Bacterial enzymes
  4. Hepatic enzymes.
  • In drug design, drug candidates may have good drug likeness but fail on first-pass metabolism, because it is biochemically selective.
DRUGS PROPERTIES:
  • Drugs with high first pass effect have a considerably higher oral dose than sublingual or parenteral dose.
  • There is marked individual variation in the oral dose due to differences in the extent of first pass metabolism.
  • Oral bioavailability is apparently increased in patients with severe liver diseases like Cirrhosis.
  • It is increased if another drug competing with it in first pass metabolism given concurrently. Eg. propranolol and chlorpromazine
ALTERNATIVE ROUTES OF ADMINISTRATIONS:
  • Avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation.
  • Suppository,
  • Intravenous,
  • Intramuscular,
  • Inhalational aerosol,
  • Transdermal and
  • Sublingual
EXTENT OF FIRST PASS METABOLISM :

LOW INTERMEDIATE HIGH-NOT GIVEN ORALLY HIGH ORAL DOSE
Phenobarbitone Aspirin Isoprenaline Propranolol
Phenylbutazone Quinidine Lignocaine Alprenolol
Tolbutamide Desipramine Hydrocortisone Verapamil
Pindolol Nortriptyline Testosterone Salbutamol
Exam Question
  • A drug administered through Oral route undergo high first pass metabolism
  • High first pass metabolism Causes for less bioavailability
  • High first pass metabolism is seen in Lignocaine, Propranolol & Salbutamol
  • Isosorbide mononitrate passes by first pass metabolism
  • Sublingual route escape first pass metabolism
  • Theophylline escape first pass metabolism
Don't Forget to Solve all the previous Year Question asked on First pass metabolism