Drug Elimination - Metabolism and Excretion Flashcards
What factors affect bioavailability?
- Absorption i.e drug solubility
- Metabolism i.e first pass metabolism - if high, then bioavailability is low
Why are larger oral doses usually administered and what could be an alternative?
- Drugs undergo first pass metabolism.
- Reduced concentration reaches systemic circulation and act on receptors.
- EXCEPTION - hepatic cancer.
- ALTERNATIVE - different route of administratione.g IV
Describe the main effects of drug metabolism.
- Reducing lipid solubility of drugs by introducing hydrophilic components to allow efficient elimination
- Main site - the liver
- Altered biological activity of drug
- EXAMPLES: pharmacological (in)activation. Conversion to (in)active derivatives
Describe phased metabolism.
- DRUG TO DERIVATIVE - Phase 1
- DERIVATIVE TO CONJUGATE - Phase 2
- Some drugs directly enter Phase 2
Describe phase 1 metabolism of aspirin.
- Hydrolysis to salicylic acid - pharmacologically active
What are the types of Phase 1 reactions?
- Oxidation and reduction - by cytochrome P450 enzymes
- Usually form more chemically reactive products
- Prepare for Phase 2 metabolism
Describe Phase 2 metabolism of aspirin.
- Functional group undergoes conjugation reactions
- Typically decreases lipid solubility and products are not pharmacologically active
- Conjugate excreted in urine
- EXAMPLE: Glucuronidation
What is special about paracetamol metabolism?
- Greater proportion of drug directly enters Phase 2 metabolism
- Smaller proportion forms toxic intermediates
What occurs during paracetamol overdoses?
- Usually toxic intermediate are detoxified via conjugation
- GSH becomes depleted, so NAPQI accumulates
- Toxic effects
- Treated by charcoal (if arriving at A&E within 2 hours) and N-acetylcysteine
Describe the effects of phases 1 and 2 reactions on drug polarity.
- PHASE 1 - less polar
- PHASE 2 - more polar
What are the major routes of drug excretion?
- Kidney (via urine)
- Hepatobiliar system (in faeces) - determined by molecular weight of drug > 4000 Da
- Lungs - for volatile compounds e.g anaesthetics
Describe drug excretion threough the bile.
- Molecular weights of around 500Da optimal for biliary excretion
- Glucuronide conjugates of MW > 400 Da tend to be excreted in bile. Less than 400 Da excreted in urine
Glucuronide conjugates excreted in bile may undergo enterohepatic circulation. Describe this process.
- Drug metabolised to conjugate in liver
- Conjugate excreted in bile from gall bladder into gut
- Conjugate bacterially hydrolysed back to drug and free glucuronide
- Drug reabsorbed in portal vein. Transported back to liver.
- Parent drug reabsorbed into blood - prolonged duration of action
Describe the therapeutic effects of enterohepatic circulation.
- Reservoir of re-circulating drug, increases half-life
- Provides options when needed to treat patients with renal dysfunction
Describe renal drug excretion.
- Can occur thorugh glomerular filtration, active tubular secretion, passive diffusion across tubular epithelium
- Rate of renal excretion varies
- Metabolites cleared faster than parent drug
Describe drug renal excretion through glomerular filtration.
- Drugs of MW < 20,000 Da diffuse into glomerular filtrate
- Plasma albumin and plasma bound proteins held back
- Lipid solubility and pH don’t affect filtration - determined by size
Describe renal drug excretion by active tubular secretion. PART 1
- Drugs transported to proximal tubular lumen by organic anion/cation transporters
- Acidic drugs e.g penicillin use OATs. Organic bases e.g morphine use OCTs
- Plasma protein binding not barrier to carrier mediated transport
- Carrier systems can transport drugs against electrochemical gradient - requires energy
Describe renal drug excretion by active tubular secretion. PART 2
- Not affected by pH
- Many drugs share same transporter - leads to competition
- Most effective mechanism for elimination
Describe renal penicillin excretion.
- 80% plasma protein bound
- Cleared slowly by filtration
- Almost completely cleared by proximal tubular secretion
- HIgh rate of elimination
- Probenecid developed to inhibit tubular penicillin secretion by competing for OAT
Describe renal drug excretion by tubular reabsorption. PART 1
- As water reabsorbed, drug concentration in urine increases
- Highly lipid soluble diffuse readily back to bloodstream. Slow excretion
- Highly water soluble drugs can’t - concentrate in urine
- Polar drugs not readily reabsorbed
Describe renal drug excretion by tubular reabsorption. PART 2
- Urine pH varies depending on drug or diet
- Changes in urine pH alters drug ionisation and therefore excretion. Can result in ion trapping
