Drug Metabolism And Elimination

Question 1

Discuss the importance of drug metabolism; dosing and safety

Answer 1

Dosing issues
–Metabolism / clearance determine the amount of drug available at site of action,
–Time taken for a drug to reach steady state levels
•Safety issues
–Metabolism produces new chemical entities that may have their own effects
–Components of racemic molecules (D/L) handled differently

• Knowledge can aid design of future drugs
• Drug metabolites measured in substance abuse tests

Drug removal begins immediately
•Most undergo metabolism prior to removal – to increase excretion
•Loss of (or reduced) biological activity
•increase polarity/less receptor binding

• Some drugs are “activated” by metabolism (prodrug)
• e.g. enalapril into active form enalaprilat by esterases
• Some drugs eliminated unchanged
• e.g. digoxin
• Toxic metabolites

Question 2

Define and describe the two phases of drug metabolism

Answer 2

Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
•Achieved by converting drugs into water-soluble molecules
•Mostly in the liver, but also in plasma, lung and intestinal

Phase 1 introduces chemically reactive groups

• Main process is oxidation within the liver
• Addition of oxygen molecules to carbon, nitrogen, sulphur molecules in drug structure

•Carried out by cytochrome P450 enzymes (huge superfamily of enzymes in liver)
– bind drug + molecule oxygen
– oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water

•Other reactions : hydrolysis, hydration etc

Phase 2 increases water solubility of drug for excretion

• conjugates the Phase 1 product with an endogenous substance through production of stable covalent bonds
• e.g. glucuronidation (reaction with glucose)

Question 3

Describe the role of drug metabolism in paracetamol overdose

Answer 3

Phase 1 metabolism significant only when glucuronidation and sulphate conjugation saturated CYTOCHROME P450
TOXIC QUINONE-IMINE

Question 4

Describe factors that influence drug metabolism and excretion

Answer 4

• Age
  
  • Cyto P450 activity reduced in neonates/elderly
  • GFR reduced greatly in neonates/elderly
  • Increased % fat content in elderly

•Genetics

• 45% in Europe & USA; 80-90% Asians fast acetylators
• 1/3000 slow metabolism by pseudocholinesterase

Drug metabolising enzymes

• Can be induced by other drugs or lifestyle factors
• Can be inhibited by other drugs or lifestyle factors

•Disease

• Liver disease impairs drug metabolism - drug toxicity
• Renal disease may alter pharmacokinetics

Question 5

Describe the pharmacokinetic considerations when prescribing

Answer 5

-For drugs that have a narrow therapeutic index

• For drugs concentrations that relate well to either therapeutic effect or toxic effect, or both
• To individualise therapy
• To confirm adherence of therapy
• To diagnose toxicity
• To determine the presence of other drugs before starting therapy
• As part of post-marketing surveillance to detect drug-drug interactions