Drug metabolism and excretion Flashcards
What is drugs in circulation determined by?
Determined by supply rate and removal from the body
Process of elimination(metabolism)
• Metabolism
○ Removal of lipid soluble drug molecules to prevent reabsorption by kidneys
○ Achieved by converting drugs into water soluble molecules
○ Mostly in liver but also in plasma, lung and intestinal epithelium
Process of elimination(Excretion)
• Excretion
○ Removal of drug/metabolites from the body
○ Mostly in urine but also via bile, sweat, tears, saliva, nce for drugs following 1st order kinetics
What is the plasma CL for a drug which is removed by liver metabolism and kidney excretion?
Plasma CL=hepatic CL+ renal CL
Importance of drug metabolism and excretion(Dosing issues)
• Dosing issues:
○ Metabolism/clearance determine the amount of drug available at site of action
Time taken for a drug to reach steady state levels
Importance of drug metabolism and excretion(Safety issues)
○ Metabolism produces new chemical entities that may have their own effects
○ Components of racemic molecules handled differently
When does drug removal begin?
• Drug removal begins immediately
what do most drugs undergo?
• Most undergo metabolism prior to removal to increase excretion
○ Loss of biological activity by
§ Increase in polarity
§ Less receptor binding
How are some drugs activated?
Some drugs activated by metabolism(prodrug)
How are some drugs eliminated?
• Some drugs are eliminated unchanged
2 phases of drug metabolism
• Phase 1:
○ 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
§ Bind drug and molecule of oxygen
§ Oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
○ Other reactions are hydrolysis and hydration etc.
○ Mainly by CYP isoforms
• Phase 2:
○ Increases water solubility of drug for excretion
○ The product of phase one is conjugated with an endogenous substance through production of stable covalent bonds
Excretion via the kidneys(Glomerulus filtration)
○ Filters <20kDa molecules
○ Amount excreted depends on levels of drug bound to plasma proteins
Excretion via the kidneys(Reabsorption)
○ As molecules pass through tubules, they are concentrated
§ Creates large concentration gradient for reabsoprtion
Hence need to make drugs water soluble
Excretion via the kidneys(Tubular secretion)
○ Acid/base molecule carriers transport molecules into tubular fluid
○ Lower levels of unbound drug in plasma, pushing reaction for plasma protein to release more free drug for secretion by carriers
○ Excretion=filtration-reabsorption+secretion
What is renal clearance?
Volume of plasma cleared of drug per unit time in one pass through kidney
What happens in renal clearance as drug is cleared in renal clearance?
• Drug is cleared from blood and appears in urine
What happens as renal elimination decreases?
As renal elimination decreases, plasma half life increases
Factors affecting drug metabolism and excretion(Age)
• Age
○ Cyto p450 activity reduced in elderly
○ GFR reduced greatly in elderly
○ Increased % fat content in elderly
Factors affecting drug metabolism(Genetics)
• Genetics
○ 45% in west and 80-90% in east have fast acetylators
○ 1/3000 slow metabolism by pseudocholinesterase
Factors affecting drug metabolism(Drug metabolising enzymes)
• Drug metabolising enzymes:
○ Can be induced by other drugs or lifestyle factors
○ Can be inhibited by some drugs
Factors affecting drug metabolism(Disease)
• Disease:
○ Liver disease impairs drug metabolism-drug toxicity
○ Renal disease may alter pharmacokinetics
Why is drug concentration monitored?
- For drugs that have a narrow therapeutic index
- For drugs concentrations that relate well to either therapeutic effect or toxic effect
- To individualise therapy
- To confirm adherence of therapy
- To diagnose toxicity
- To determine presence of other drugs before starting therapy
- Post marketing surveillance to detect drug-drug interactions
