Basic Pharmacology

Alteration of drugs by the liver. Drugs can be metabolized from active to inactive, or from inactive to active. Generally drugs are made more hydrophilic by the process.

• PHASE I: Mixed-Function Oxidases, formed by microsomes made out of Smooth-ER folded over on itself.
  • Cytochrome-P450 Enzyme Complex: Has four required components in order to work.
    • Cytochrome-P450 Enzyme
    • Cytochrome-P450 Reductase
    • O₂
    • NADPH: NADPH is the only energy source. No ATP is required!
  • Phase I enzymes perform multiple types of reactions:
    • OXIDATIVE REACTIONS: on drugs, such as: Aromatic hydroxylation, aliphatic hydroxylation, N-dealkylation, O-dealkylation, S-dealkylation, N-Oxidation, S-Oxidation, Desulfuration.
    • REDUCTIVE REACTIONS: Azo, Nitrile, Carbamyl
    • HYDROLYTIC REACTIONS: Ester hydrolysis, Amide hydrolysis.
• PHASE II: Drug Conjugation. usually to glucuronides, making the drug more soluble.
  
   

CYTOCHROME-P450 COMPLEX:

• There are multiple isotypes.
  • CYT-P450-2 and CYT-P450-3A are responsible for the metabolism of most drugs.
  • CYT-P450-3A4 metabolizes many drugs in the GI-Tract, where it decreases the bioavailability of many orally absorbed drugs.
• INDUCERS of CYT-P450 COMPLEX: Drugs that increase the production of Cytochrome-P450 enzymes.
  • ANTI-CONVULSANTS: Phenobarbitol, Phenytoin, Carbamazepine induce CYT-P450-3A4
  • Phenobarbitol, Phenytoin also induce CYT-P450-2B1
  • Polycyclic Aromatics (PAH): Induce CYT-P450-1A1
  • Glucocorticoids induce CYT-P450-3A4
  • Chronic Alcohol, Isoniazid induce CYT-P450-2E1. This is important as this drug activates some carcinogens such as Nitrosamines.
    • Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.
• INHIBITORS of CYT-P450 COMPLEX: Drugs that inhibit the production of Cytochrome-P450 enzymes.
  • Acute Alcohol suppresses many of the CYT-P450 enzymes, explaining some of the drug-interactions of acute alcohol use.
  • Erythromycin, Ketanazole inhibit CYT-P450-3A4.
    • Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds up in the presence of Erythromycin. The unmetabolized form is toxic and causes lethal arrhythmias. This is why Seldane was taken off the market.
  • Chloramphenicol, Cimetidine, Disulfiram also inhibit CYT-P450's.
    
     

EXCRETION:

• KIDNEY
  • GLOMERULAR FILTRATION: Clearance of the apparent volume of distribution by passive filtration.
    • Drug with MW < 5000 ------> it is completely filtered.
    • Inulin is completely filtered, and its clearance can be measured to estimate Glomerular Filtration Rate (GFR).
  • TUBULAR SECRETION: Active secretion.
    • Specific Compounds that are secreted:
      • para-Amino Hippurate (PAH) is completely secreted, so its clearance can be measured to estimate Renal Blood Flow (RBF).
      • Penicillin-G is excreted by active secretion. Probenecid can be given to block this secretion.
    • Anionic System: The anionic secretory system generally secretes weak ACIDS:
      • Penicillins, Cephalosporins
      • Salicylates
      • Thiazide Diuretics
      • Glucuronide conjugates
    • Cationic System: The cationic secretory system generally secretes BASES, or things that are positively charged.
    • Ion-Trapping: Drugs can be "trapped" in the urine, and their rate of elimination can be increased, by adjusting the pH of the urine to accommodate the drug. This is useful to make the body get rid of poisons more quickly.
      • To increase excretion of acidic drugs, make the urine more basic (give HCO₃^-)
      • To increase excretion of basic drugs, make the urine more acidic.
• BILIARY EXCRETION: Some drugs are actively secreted in the biliary tract and excreted in the feces. Some of the drug may be reabsorbed via the enterohepatic circulation.
  • Transporters: The liver actively transporters generally large compounds (MW > 300), or positive, negative, or neutral charge.
    • Anionic Transporter: Transports some acids, such as Bile Acids, Bilirubin Glucuronides, Glucuronide conjugates, Sulfobromophthalein, Penicillins
    • Neutral Transporter: Transports lipophilic agents, such as:
      • Steroids
      • Ouabain
    • Cationic Transporter: Transports positively charged agents, such as n-Methylnicotinamide, tubocurarine.
  • Charcoal can be given to increase the fecal excretion of these drugs and prevent enterohepatic reabsorption.
  • Cholestyramine can be given to increase the rate of biliary excretion of some drugs.