General and Systematic Veterinary Pharmacology

ENZYME INDUCTION AND INHIBITION

Enzyme inhibition

• Some drugs on repeated administration have the ability to “inhibit” cytochrome P-450 enzyme activity.
• These drugs cause a reduction in the metabolism of other drugs that are adminstered subsequently.
• Some drugs that act as inhibitors are chloramphenicol, cimetidine, dicumarol, oral contraceptives, ethanol and isoniazid. This is an immediate process due to direct inhibition of the enzyme or competition among drugs for the enzyme site
• As a result the concentration of drug increases leading to increased drug effect
  

Enzyme induction or stimulation

• Some drugs on repeated administration have the ability to “induce” cytochrome P-450 by enhancing its rate of synthesis or by reducing its rate of degradation.
• Induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic action of the inducer and also of coadministered drugs.
• Increase in enzyme concentration due to induction of protein synthesis ( hence called INDUCERS) and takes long time to set in and once the inducing drug is stopped, takes long time to return to original values.
• Some drugs that act as inducers are griseofulvin, phenobarbital, phenylbutazone, phenytoin and rifampin.

Significance of enzyme induction / inhibition

• Inhibitors prolong the activity of co-administered drugs
• It also increases the toxic effects of unchanged drugs, if any
• Drug metabolism varies in smokers and alcoholics ( in human patients)
• In case of combined administration, alteration of dose may be required

Factors affecting biotransformation

• Age: Biotransformation is poor in neonates since enzyme systems are not well developed. Biotransformation is poor in old animals, too
• Disease: Diseases of the liver- hepatitis, cirrhosis etc.. and also diseases causing low blood flow to liver such as CHF, shock etc. will alter biotransformation
• Species differences:
  • Cats are deficient in glucuronidation (low level of glucuronyl transferase)
  • Dogs lack acetylation
  • Pigs have low capacity for sulfation
  • Genetic differences do exist in human races in metabolizing many drugs ( eg.. metoprolol in man)
  • Losartan – an antihypertensive – effective in man but less so in dogs since the active metabolite is not formed in dogs
  • Rabbits possess atropinase – therefore do not suffer from toxicity due to atropine (in deadly night shade poisoning)
• Co-administration of other drugs – inducer or inhibitor
• Habits like alcoholism and smoking or industrial pollutants, pesticides may alter metabolism of some drugs

First pass metabolism

• Refers to the process of metabolism of a drug before it reaches systemic circulation.
• Normally happens in drugs administered by oral route. Besides oral route, it can occur in topical (skin) and lungs, too (however at low levels)
• Effects of first pass metabolism:
  • Increased oral dose of the drug
  • Unpredictable absorption of oral dose variation among individuals in drug action
  • Oral bioavailability increased, if there is liver disease

Enterohepatic recirculation

• Some drugs after biotransformation by glucuronide conjugation, undergo biliary excretion. In the large intestine they are detached from the conjugate, leading to release of free drug which is absorbed again and enters liver. Thus the drug recirculates leading to longer duration of action.
• Eg: Phenalpthaelin used as purgative.