Clearance of drugs from the body

Question 1

How are drugs cleared from the body (4)

Answer 1

1. Some drugs are metabolised
2. Some drugs are excreted in the faeces
3. Some (i.e. water soluble) drugs are excreted unchanged in the urine
4. Some drugs cleared by multiple organs (but predominantly by one)

Question 2

What do we mean by Clearance? (7)

Answer 2

1. “The volume of blood that is effectively cleared of drug in a given time period”
2. Usually expressed in L/hr
3. Liver and kidney responsible for most clearance
4. Water soluble drugs excreted unchanged in urine
5. Metabolites may be inactive
6. Some contribution from gut wall, biliary tract and other organs
7. Affected by blood flow, organ function and protein binding

Question 3

What is the extraction ratio (4)

Answer 3

1. Efficiency of an organ at clearing a drug
2. ER = (Concentration entering organ - concentration leaving)/Concentration entering organ
3. Thus, predominantly affected by blood flow, organ functionality and protein binding
4. If ER = 1, all blood passing through organ is removed of drug

Question 4

What is the elimination rate constant (4)

Answer 4

1. Fraction of drug elimination per unit of time
2. Usually hr-1
3. Therefore, if K = 0.1 = one tenth (or 10%) of drug available eliminated per hour
4. Clearance = K x Vd

Question 5

What is half-life (2)

Answer 5

1. Time it takes for amount to drug in the body to halve
2. Half-life = ln2/k

Question 6

What is first order elimination (3)

Answer 6

1. “First Order” i.e. the rate of a process is directly proportional to the amount of drug available for the process
2. Most drugs at therapeutic doses
3. “Linear kinetics”

Question 7

What is zero order/non-linear kinetics (7)

Answer 7

1. After a point, rate of elimination process not proportional to amount of drug. Usually due to enzyme saturation → accumulation of excess drug
2. Saturation point varies between patients
3. Get higher than expected rise in plasma concentration for smaller dose increases
4. At therapeutic doses - Half-life increases with plasma concentration
5. In overdose, theophylline can obey zero order kinetics. Alcohol also obeys zero order kinetics
6. Amount of drug eliminated per unit of time is constant – the proportion of drug eliminated falls as plasma concentrations rise.
7. Therefore, effect of drug dose increases are less predictable than with drugs that have linear (first order) kinetics.

Question 8

What affects hepatic clearance (6)

Answer 8

1. Hepatic blood flow
2. Hepatic intrinsic clearance (ability of liver to metabolise drug in absence of restricted drug delivery)
3. Drugs with high intrinsic hepatic clearance - Metabolic rate depends on blood flow
4. Drugs with low intrinsic hepatic clearance - Hepatic blood flow has minimal influence on metabolic rate
5. Need to consider nature of metabolites (i.e. active vs inactive) - Patients with renal impairment will accumulate metabolites
6. Hepatic metabolism implicated in the majority of pharmacokinetic drug-drug interactions (i.e. enzyme induction or inhibition)

Question 9

What is the hepatic extraction ratio (8)

Answer 9

1. Fraction of drug in blood removed by one “pass” through the liver
2. Hepatocytes can only extract (metabolise) unbound drugs
3. Increased hepatic blood flow will decrease extraction ratio
4. More significant if intrinsic hepatic clearance for drug is low
5. If intrinsic hepatic clearance is high, enzyme system can cope, and extraction ratio falls minimally
6. Drug delivery to the cell = hepatic blood flow and protein binding
7. Hepatocytes only have access to free (unbound) drug.
8. Increased hepatic blood flow increases amount of drug presented to liver

Question 10

How can first-pass metabolism be avoided (5)

Answer 10

1. Change route of administration of the drug
2. Glyceryl trinitrate – use sublingual tablets or spray
3. Testosterone – use injection or transdermal gel
4. Salbutamol – use inhaled route
5. Remdesevir – given intravenously

Question 11

What are the effects of drug interactions (5)

Answer 11

1. If drug has high hepatic extraction ratio – even if enzyme inhibition has small effect on first pass metabolism, there’s a clinically significant changes in bioavailability
2. E.g. if ER = 0.95, bioavailability = 0.05 → if ER reduced to 0.9 (small decrease), bioavailability increases to 0.1 (i.e. doubles)
3. If a drug has a low extraction ratio (e.g. ER = 0.05; bioavailability = 95%):
4. Halving ER (to 0.025) → bioavailability increases to 0.975 (97.5%)
5. Reducing ER to a 10th of original value (to 0.005) → bioavailability increases to 0.995 (99.5%)

Question 12

What is renal clearance (4)

Answer 12

1. Water soluble drugs excreted unchanged
2. Water soluble metabolites excreted in urine
3. Active vs inactive
4. renal clearance = renal extraction rate (mg/min) / Drug plasma concentration (mg/L)

Question 13

What are the mechanisms involved in renal clearance (4)

Answer 13

1. Filtration
2. Active secretion
3. Reabsorption
4. Some drug metabolism

Question 14

How does filtration affect drug clearance (4)

Answer 14

1. Drugs bound to large blood constituents (e.g. plasma proteins) won’t be effectively filtered
2. If drug is filtered freely and has no secretion or reabsorption:
3. CLR = Glomerular Filtration Rate (GFR)
4. Estimated creatinine clearance (eCrCl) common method for assessing renal function (GFR)

Question 15

What is active secretion (5)

Answer 15

1. Carrier-mediated process
2. Tubular transporters: organic anion transporter (OAT) and organic cation transport (ACT): each has various sub-groups
3. Important for highly protein-bound drugs (not effectively cleared by glomerular filtration
4. Transporters are saturable
5. Structural analogues may compete for transport

Question 16

What is active reabsorption (4)

Answer 16

1. Many endogenous compounds (e.g. electrolytes, glucose) undergo active reabsorption (usually in proximal tubule)
2. Accumulation may occur when filtered load exceeds system capacity

Lithium has additional consideration:

1. If serum sodium levels low, kidneys try to re-absorb
2. Can’t differentiate between lithium and sodium ions → potential lithium toxicity

Question 17

What is biliary clearance (4)

Answer 17

1. Active secretion of drugs and metabolites from hepatocytes into bile
2. Transports them to gut → excretion (faeces)
3. Efficiency is highly variable as deconjugating enzymes and gut pH → lipophilic drug forms → reabsorption into plasma (enterohepatic re-cycling) – e.g. morphine, warfarin, metronidazole
4. Drugs undergoing extensive enterohepatic recycling have longer durations of action

Question 18

How does breast milk affect clearance (4)

Answer 18

1. Some drugs (and metabolites) may pass into breast milk of lactating mothers
2. Relatively minor route, but potentially significant for the baby
3. Breast milk has lower pH than plasma
4. Basic drugs concentrate in breast milk via “ion trapping” – e.g. lithium (avoid), opioids

Question 19

What factors affect blood flow (3)

Answer 19

1. Late sepsis reduces blood flow to all organs
2. Haemorrhage
3. Heart failure → reduced cardiac output

Question 20

What does understanding drug clearance allow (5)

Answer 20

1. advise on drug dose adjustments
2. Patients with hepatic impairment likely to need dose adjustments of hepatically cleared drugs
3. Patients with renal impairment likely to need dose adjustments of both renally cleared drugs and hepatically cleared drugs that have active metabolites
4. Need to also consider therapeutic window of drug and side effect profile
5. May see different routes of clearance for drugs in same class