Metabolism and Excretion

Question 1

Define elimination and clearance.

Answer 1

Excretion – process by which waste products are removed from body. Predominantly by kidney via urine, but also via bile, sweat, faeces, breath, and tears. Not all drugs are metabolised prior to excretion eg aminoglycoside antibiotics.

Renal clearance varies for different drugs, it is amount of drug removed by kidney over specific time. Extent of clearance will determine dose needed. Highly renally cleared drugs with narrow therapeutic index eg digoxin and gentamicin will need careful dosing in renal impairment.

Question 2

How does the liver metabolise drugs?

Answer 2

Hepatocytes in the liver, contain enzymes essential for metabolism

Metabolism is divided into 2 phases
- Phase 1: catalysed by cytochrome P450 enzymes
- oxidation (propranolol)
- hydrolysis (aspirin)
- reduction (methadone)
Often still chemically active
- Phase 2: conjugation by adding a glutathione, methyl or acetyl group
- More water soluble and easier to excrete
- Less active or inactive

Drugs may undergo phase 1 only, phase 2 only or more often phase 1 followed by phase 2.
Example aspirin:
- Phase 1 – hydrolysis to salicylic acid
- Phase 2 –conjugation with glycine or glucoronic acid

Question 3

What is the process of paracetamol metabolism?

Answer 3

Paracetamol – phase 1 and phase 2

• Phase 1 to toxic metabolite:
  - N-acetyl-P- benzoquinone imine (NAPQI)
  - NAPQI directly attacks cells causing liver injury
• Phase 2 reaction to non-toxic metabolites
  - conjugation with glutathione

Toxicity problems

• NAPQI is detoxified by conjugation with glutathione (phase 2)
• NAPQI not a problem at normal doses eg 4g per day
• not enough glutathione in overdose
• Treatment involves giving acetylcysteine within 8 hours

Question 4

What is first pass metabolism?

Answer 4

If a drug is extensively metabolised in the liver we say it undergoes first pass metabolism – very little drug may end up in the systemic circulation.

Oral drugs → GI tract → liver

Sublingual and buccal routes avoid first pass metabolism

Question 5

What is the impact of hepatic impairment?

Answer 5

Needs to be very severe to affect metabolism, but can lead to:

• accumulation and toxicity
• to drug being less effective (pro-drugs)

Other Effects

• Reduced clotting
• Fluid overload
• Hepatic encephalopathy
• Reduced protein binding

Question 6

How does the kidney excrete drugs?

Answer 6

Glomerular filtration

• Small drugs pass easily from blood through glomeruli
• Large drugs eg. Heparins and protein bound drugs cannot pass through

Tubular secretion

• Active process against chemical gradient
• 2 Carrier transport systems – basic drugs (amiloride) and acidic drugs (furosemide)

Tubular reabsorption
- Transported back into the blood along with water to maintain fluid volume

Question 7

How is creatinine clearance measured?

Answer 7

F x (140-age) (weight kg)
CrCl (ml/min) =  —————————————
				                 serum creatinine (micromol/L)

Question 8

What is the impact of reduced renal function on drug clearance?

Answer 8

Renally excreted drugs
- excretion is reduced causing the drug to accumulate with
potential for toxicity

Management
- give the drug less frequently (gentamicin) or give a lower dose (digoxin)

Question 9

What drugs may cause renal and hepatic impairment?

Answer 9

• ACE inhibitors (renal)
• antiepiletic drugs (hepatic)
• NSAIDs – renal impairment and increased bleeding risk in severe
  hepatic impairment with reduced clotting factor production
• Paracetamol in overdose –direct hepatic damage, toxic metabolite not
  conjugated