Drug Elimination - Metabolism and Excretion

Question 1

What factors affect bioavailability?

Answer 1

• Absorption i.e drug solubility
• Metabolism i.e first pass metabolism - if high, then bioavailability is low

Question 2

Why are larger oral doses usually administered and what could be an alternative?

Answer 2

• Drugs undergo first pass metabolism.
• Reduced concentration reaches systemic circulation and act on receptors.
• EXCEPTION - hepatic cancer.
• ALTERNATIVE - different route of administratione.g IV

Question 3

Describe the main effects of drug metabolism.

Answer 3

• 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

Question 4

Describe phased metabolism.

Answer 4

• DRUG TO DERIVATIVE - Phase 1
• DERIVATIVE TO CONJUGATE - Phase 2
• Some drugs directly enter Phase 2

Question 5

Describe phase 1 metabolism of aspirin.

Answer 5

• Hydrolysis to salicylic acid - pharmacologically active

Question 6

What are the types of Phase 1 reactions?

Answer 6

• Oxidation and reduction - by cytochrome P450 enzymes
• Usually form more chemically reactive products
• Prepare for Phase 2 metabolism

Question 7

Describe Phase 2 metabolism of aspirin.

Answer 7

• Functional group undergoes conjugation reactions
• Typically decreases lipid solubility and products are not pharmacologically active
• Conjugate excreted in urine
• EXAMPLE: Glucuronidation

Question 8

What is special about paracetamol metabolism?

Answer 8

• Greater proportion of drug directly enters Phase 2 metabolism
• Smaller proportion forms toxic intermediates

Question 9

What occurs during paracetamol overdoses?

Answer 9

• 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

Question 10

Describe the effects of phases 1 and 2 reactions on drug polarity.

Answer 10

• PHASE 1 - less polar
• PHASE 2 - more polar

Question 11

What are the major routes of drug excretion?

Answer 11

• Kidney (via urine)
• Hepatobiliar system (in faeces) - determined by molecular weight of drug > 4000 Da
• Lungs - for volatile compounds e.g anaesthetics

Question 11

Describe drug excretion threough the bile.

Answer 11

• 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

Question 12

Glucuronide conjugates excreted in bile may undergo enterohepatic circulation. Describe this process.

Answer 12

• 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

Question 13

Describe the therapeutic effects of enterohepatic circulation.

Answer 13

• Reservoir of re-circulating drug, increases half-life
• Provides options when needed to treat patients with renal dysfunction

Question 14

Describe renal drug excretion.

Answer 14

• Can occur thorugh glomerular filtration, active tubular secretion, passive diffusion across tubular epithelium
• Rate of renal excretion varies
• Metabolites cleared faster than parent drug

Question 15

Describe drug renal excretion through glomerular filtration.

Answer 15

• 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

Question 16

Describe renal drug excretion by active tubular secretion. PART 1

Answer 16

• 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

Question 17

Describe renal drug excretion by active tubular secretion. PART 2

Answer 17

• Not affected by pH
• Many drugs share same transporter - leads to competition
• Most effective mechanism for elimination

Question 18

Describe renal penicillin excretion.

Answer 18

• 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

Question 19

Describe renal drug excretion by tubular reabsorption. PART 1

Answer 19

• 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

Question 20

Describe renal drug excretion by tubular reabsorption. PART 2

Answer 20

• Urine pH varies depending on drug or diet
• Changes in urine pH alters drug ionisation and therefore excretion. Can result in ion trapping