CB - Excretion Flashcards
What are some features of CYTOCHROME-P450 enzyme? (6)
- Membrane-bound
- Part of the endoplasmic reticulum
- Occurs in phase 1 metabolism
- Haemoprotein containing Fe
- Catalyses oxidation of drug through binding with substrates O2 or CO
- Belongs to a class of enzymes called monooxygenases
What are compounds that induce (2) and inhibit (3) cytochrome P450 enzyme?
Inducible by:
- DRUGS- Phenobarbitone
- ENVIRONMENTALLY- Smoking
Inhibited by:
- Cimetidine
- Quinine
- Grapefruit juice
What are examples of non-P450 oxidations? (2)
- MAO
- ALCOHOL DEHYDROGENASE
In which organs do P450-mediated reductions occur?
Mainly in the liver
What are examples of hydrolysis reactions in drug metabolism?
Hydrolysis of:
- Esters
- Amides
Explain the difference in metabolism between Procaine and Procainamide?
Procaine is acted upon by ESTERASES
- Fast acting = rapid hydrolysis and short duration of action
Procainamide is acted upon by AMIDES
- Slow acting = slow hydrolysis and longer duration of action
What are the three types of conjugation reactions in Phase 2 metabolism?
- Glucuronidation
- Sulphation
- Acetylation
What occurs in Glucuronidation?
Glucuronic acid C6H9O6 replaces the H in -OH, -COOH, -NH2, -SO2NH-, -SH to give water-soluble inactive products
Requires activation of carbohydrate (UDPGA)
UDP-glucuronyl transferase (UDPGT) acts
What occurs in Sulphation?
A sulphate group –SO3- replaces the H in R-OH, ArOH, ArNH2, ArNHOH to give very water-soluble inactive - usually - excretory products
Sulpho-transferase
What occurs in Acetylation?
Acetate CH3CO2- replaces the H in -NH2, -SO2NH2, -NHNH2 inactivates the functional group but no real increase in water solubility
Requires activation of acetate (AcetylCoA)
N-acetyl transferase transfers the acetate to the drug
What are 6 variables affecting metabolism?
SPECIES
rats and mice differ from humans
- higher cardiac output
- greater liver blood flow
- higher rates of metabolism
GENETICS
Enzyme defects
ENVIRONMENT
Other drugs
ELDERLY
Size of liver and blood flow decreases with age
- Reduced phase 1 metabolism
YOUNG
Drug metabolising enzymes are immature in the neonatal liver
- First-pass metabolism is low
LIVER DISEASE
Anatomical changes that impair rapid uptake of lipid-soluble drugs
- Intracellular enzyme activity is reduced
What are the 3 main routes of excretion?
Lungs
- Volatile compounds only e.g. general anaesthetics, alcohol
Kidneys - urine
- Low molecular weight (20kDa) + water soluble (glomerular F)
- Active secretion + filtration of unbound (tubular secretion)
- Reabsorption – affected by urine pH (reabsorption)
Bile
- High molecular weight (>50kDa) – esp. conjugates
- Biliary metabolites may be metabolised in gut lumen and reabsorbed - entero-hepatic circulation
What occurs in Glomerular Filtration? (2)
- Small molecules are filtered through pores 7-8nm diameter
- Protein-bound drug is not filtered, but some dissociates when water is reabsorbed from the tubule
What are features of pH-dependent reabsorption? (6)
- All lipid-soluble compounds are reabsorbed from the tubule and returned to the circulation until they are metabolised to water-soluble products
- Drug concentrates in the fluid in which it is most ionised (pH.partioning)
- Weak acids can be reabsorbed into the plasma
- Weak bases are excreted in the urine
- NaHCO3 increases urine pH (alkalinases) and enhances elimination of acids
- NH4Cl reduces urine pH (acidifies) and enhances elimination of bases
What are features of Renal Tubular Secretion? (3)
- Different transporters for acids and bases
- An active process that can strip a drug from protein-binding sites
- Many drug conjugates are substrates for active secretion
