Lecture 6 - How are drugs metabolised in the body?

Question 1

Describe the 2 biochemical reactions involved in drug metabolism

Answer 1

Phase 1 catabolic (breaking down) reactions - can produce more ‘reactive’ compound

Phase 2 synthetic (anabolic) reactions - involve conjugation to produce inactive product

Question 2

Describe the livers’ role in drug metabolism

Answer 2

• ‘microsomal’ enzymes (intracellular) - e.g. cytochrome P450, alcohol dehydrogenase, MAO
• drugs must cross plasma membrane (lipid soluble or bind to specific transporter) to be metabolised)
• some drugs ‘pro-drugs’ only become active after metabolised
• metabolism can alter or prolong pharmacological actions of a drug

Paracetamol metabolism creates hepatotoxic molecule. Many benzodiazepines are metabolised into long-lived active metabolites - so get sedation even after parent compound has disappeared.

Some drugs increase the activity of Microsomal enzymes and conjugating systems

Question 3

Describe induction for metabolism to occur

Answer 3

• involves increased synthesis of the enzymes
• can increase or decrease drug toxicity
• e.g. paracetamol, phase 1 metabolite is TOXIC, therefore toxicity may be increased following enzyme induction
• many anticonvulsants (e.g. carbamazepine) used in treatment of epilepsy cause enzyme induction, so does ethanol

Question 4

Describe the elimination of aspirin

Answer 4

Aspirin (drug) –> salicylic acid (derivative & active metabolite) –> Glucuronide (conjugate - allows for excretion)

Products of phase 1 reaction may have increased toxicity and carcinogenicity. In some cases, e.g. Morphine-6-glucoronide being developed as analgesic, causing less nausea, perhaps because more polar has less access to vomiting centres.

Not all drugs metabolised by p450, e.g. Alcohol metabolised by alcohol dehydrogenase, some amines by MO (monoamine oxidases). Aspirin is hydrolytic - reactions can occur in plasma and tissues.

Question 5

How many genes have been identified to code for p450 enzymes?

Answer 5

Human genome project identified 57 genes

Question 6

What are p450 enzymes involved in?

Answer 6

drug metabolism, steroid synthesis, and the breakdown of toxins. This often involves oxidation (adding oxygen to) substrates, which often makes them more water-soluble and easier to eliminate from the body.

Question 7

What carries out phase 1 reactions?

Answer 7

Cytochrome P450 family of enzymes - 3 of the main genes identified to code for these enzymes are used to metabolise drugs found in the liver.
- get variations among individuals (polymorphisms) and species
- P450 enzymes have therapeutic implications

Question 8

What else can influence activity of some enzymes?

Answer 8

Environmental factors - e.g. grapefruit juice inhibits some enzymes (cardiac dysrhythmias), where as Brussel sprouts and cigarette smoke can induce P450

Question 9

What is important to note about metabolism of drugs with similar targets/functions?

Answer 9

May be metabolised by different isoforms of P450 e.g. NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

Question 10

Explain how inducers of P450 increase drug metabolism

Answer 10

Enzyme induction (results in increased levels of activity of the enzyme) can INCREASE drug toxicity and carcinogenicity if product of phase 1 reaction (e.g. paracetamol) are toxic. Other factors inhibit P50 enzymes - e.g. grapefruit juice - serious consequences, heart dysrhythmias.

Note this is not the only system used for drug metabolism - there are other enzymes too - this is just an example of a common mechanism and gives an insight why you can get many variations between patients, but also species and need to be considered when testing new drugs

Question 11

Describe how drugs are eliminated from the body

Answer 11

Action terminated

Renal excretion
- glomerular filtration
- active tubular secretion
- passive diffusion

Question 12

How do chemical properties of drugs have an impact on their excretion?

Answer 12

Penicillin cleared from the blood on single transit vs diazepam (highly lipophilic and makes active metabolites cleared very slowly)

renal disease can affect drug clearance - toxicity
1. GI excretion
2. Lung excretion

Question 13

Does dosing regime alter time takes to reach steady state?

Answer 13

No, but number of doses needed dose vary
- predicting time course of drug action is very important clinically, since it underpins the dosing regime.

Question 13

Describe the 3 route excretion occurs via the kidneys

Answer 13

Glomerular filtration - most drugs (<20kDa mw) unless highly protein bound - albumin has molecular weight 68 kDa

Active tubular secretion - weak acids and bases, rapid drug elimination e.g. via OAT and OCT transporters. Also works with protein bound drugs

Passive diffusion - across tubular epithelium. Lipid-soluble drugs, inefficient excretion

because of pH partition, weak acids are more rapidly excreted in alkaline urine and vice versa

**toxicity may occur in elderly or patients with renal disease

Question 13

Describe the curve of drug concentrations in the body over time

Answer 13

Mono-exponential delay, the time course of which is determined by rate of metabolism and excretion

Question 14

What is the single-compartment model?

Answer 14

Drug is distributed into one homogenous compartment - e.g. following intravenous injection, and then is ‘cleared’ by combination of metabolism and excretion.

• in such situation, the concentration of the drug in the plasma follows ‘first-order’ kinetics, where rate of elimination is directly proportional to drug concentration.

Question 15

What happens when you give continuous or repeated doses?

Answer 15

With continuous infusion, drug concentration in plasma increases overtime to a steady state level where rate of infusion is matched by rate of elimination.

With repeated doses, get similar behaviour - i.e. reaches steady state is independent of route of dosing regime, but number of doses needed to reach steady state DO vary with dosing regime

Question 16

How many half lives of a drug is needed to reach the steady state?

Answer 16

usually 3.5 half lives

Question 17

Why do drugs not behave like this in reality?

Answer 17

As they distribute among different compartments and in this case, much more difficult to predict drug concentrations. Really complicated mathematical models used instead.

Question 18

Describe how the time course of drug concentration is different for drugs with saturating kinetics

Answer 18

Disproportionate increase in steady-state plasma concentration –> clinical side effects, toxicity