Case 6 - Hepatic Drug Metabolism

Question 1

The Four Main Processes Involved in Drug Therapy

Answer 1

Pharmaceutical Process:
getting the drug into patient

Pharmacokinetic Process:
getting drug to the site of action

Pharmacodynamic Process:
producing required pharmacological effect

Therapeutic Process:
Pharm effect translated to a therapeutic effect

Question 2

The liver has evolved as the organ of ___1___in the body to breakdown anything that poses a biochemical threat caused by chemical toxicity. Hepatic enzymes will create drug metabolites ready for ___2___which it does in two Phases, Phase __3__and Phase __4__.

Answer 2

1 - detoxification
2 - excretion
3 - I
4 - II

Question 3

Inert metabolites from drug metabolism can
be moved via ___1_____ into the ___2___ and then into the gut lumen. Alternatively, the metabolites are transported in the ___3___to the kidneys for excretion into the __4__

Answer 3

1 - P-glycoprotein transporters
2 - bile duct
3 - bloodstream
4 - urine

Question 4

Permeability glycoprotein (P-gp) can be found where?

Answer 4

on the apical/luminal membrane of intestinal epithelial cells, on the canalicular membrane of human hepatocytes, and on the apical/luminal membrane of renal proximal tubule cells

Question 5

Metabolism switches off what?

Answer 5

Metabolism switches off pharmacological activity through enzyme activity rendering it
inert and turning the drug into water soluble metabolite in water or faeces.

Question 6

Biotransformation takes place
predominantly where?

Answer 6

in smooth endoplasmic reticulum.

Question 7

The speed at which a drug is metabolised is a function of what?

Answer 7

a function of the enzyme kinetics

Question 8

A drug is simply a ___1____for a particular enzyme and the enzyme will convert that
substrate into a product or ‘metabolite’.

Answer 8

1 - substrate

Question 9

If the drug dose exceeds the enzyme ___1___concentration, unmetabolised drug may build up to ___2___levels and/or the excess drug may be metabolised by other enzymes into ___3___.

Answer 9

1 - Vmax
2 - toxic
3 - toxic species

Question 10

what do Phase I enzymes typically do?

Answer 10

Phase I enzymes typically add or create chemically reactive groups to the drug.

Question 11

Depending on the metabolic pathway and the specific drug, a number of Phase I
enzymes may sequentially alter and modify the original drug structure. Such
enzyme-mediated reactions may include:

Answer 11

oxidation, reduction and esterification; all
with an aim to facilitate drug deactivation in Phase II.

Question 12

Phase I metabolites may actually be ______ biologically active than the parent drug molecule

Answer 12

more

Question 13

A prodrug is an inactive or less active form of a drug that becomes active only after it is metabolized in the body.

3 reasons to give a prodrug

Answer 13

non toxic, can be converted quickly without degradation, can move around the body easily

Question 14

Therapeutically, intermediate Phase 1 metabolites can be exploited to switch pro
drugs on. Give an example

Answer 14

For example, ramipril is a drug used to treat high blood pressure (Angiotensin Converting Enzyme inhibitor), but it is inert until it reaches the liver where hepatic esterases modify the drug to ramiprilat which is the
pharmacologically active drug able to lower BP.

Question 15

some Phase 1 metabolites
may be very cytotoxic. If these toxic intermediates build up and are present for long enough, extensive ______to tissues can result.

Answer 15

damage

Question 16

Phase 2 processes often achieve ___1___deactivation and water
___2___at the same time by chemically ___3___out a drug’s pharmacophoric region (i.e., the element that confers biological activity) with a ___4___ such as a sugar or a sulfo group.

Answer 16

1 - biochemical
2 - solubilisation
3 - swapping
4 - water-soluble component

Question 17

what is the most significant enzyme family of phase I enzymes?

Answer 17

(Cytochrome P450 enzymes) CYP enzymes

Question 18

what are CYP enzymes responsible for?

Answer 18

They are responsible for the majority
of oxidative modifications to
drugs, usually in advance of
Phase II metabolic processes

Question 19

CYPs are ‘on demand’ enzymes - what’s this mean?

Answer 19

CYPs are induced only when the drug or toxin they metabolise is present.

Question 20

what is at the centre of CYP and forms the active site?

Answer 20

Haem

Question 21

what is a major class of Phase II enzymes?

Answer 21

UDP-glucuronosyl transferases (UGTs)
are a major class of Phase II enzymes.

Question 22

how do UDP-glucuronosyl transferases (UGTs) work?

Answer 22

They conjugate a water
soluble glucuronide (sugar) molecule
on to the drug or toxin metabolite. This
renders the drug/toxin inactivated and
suitable for water-soluble
excretion either into the urine via renal
excretion or into the lumen of the gut
via hepatobiliary excretion.

Question 23

what can lead to Gilbert’s or Crigler
Najjar syndromes?

Answer 23

Polymorphisms (or deletions) of UGT1A1 where bilirubin cannot be glucuronidated (not conjugated with glucuronic acid to make water soluble to easily excrete from body) and
excreted at the required rate and levels.
due to the deficiency of UGT1A1 enzymes → bilirubin doesn’t get conjugated and so there’s increased unconjugated bilirubin.

[Genotype testing can be helpful in
determining the specific type of jaundice a
patient presents with.]

Question 24

Drug-Drug Interactions

Answer 24

Drug-drug interaction:
Drug A induces a quantity of enzyme that
metabolises drug A and reduces the dose of
drug A at the expected rate.
Drug B will also induce the same enzyme. Not only will drug B be metabolised but the extra quantity of enzyme that has been
induced by drug B will also accelerate the
metabolism of drug A. This may lead to drug A being metabolised before it can have its therapeutic effect.

Question 25

Competitive inhibition of drug-drug interaction

Answer 25

Drug A and drug B are both metabolised by the same enzyme. But drug B is the preferred substrate for the enzyme so will occupy the active site more than drug A. Drug B can said to be ‘competitively inhibiting’ drug A’s metabolism. If this is not taken into consideration, repeat dosing of drug A may lead to a build up to toxic levels as it is not being metabolised at the expected rate in the presence of drug B.

Question 26

what is a toxic does of paracetamol and what is lethal?

Answer 26

each tablet of paracetamol is 500mg 4 g - 6 g is a toxic dose >12 g may be lethal

Question 27

The longer the NAPBQI is present in the liver, what happens?

Answer 27

The longer the NAPBQI is present in the liver, the more extensive and irreversible the damage caused by paracetamol

Question 28

Infusing a patient with IV n-acetyl cysteine (NAC) allows what?

Answer 28

allows hepatic glutathione levels to be replenished and allows the glutathione to effectively mop up and de-activate any NAPBQI present. [As a rule, the quicker an NAC infusion can be started on a paracetamol OD (overdose) patient, the better their prognosis.]

Question 29

what are the 2 pathways of paracetamol mechanism's (no overdose, just normal)

Answer 29

2 x 500mg - majority of the dose is directly glucuronidated by UGTs, bypassing Phase I enzymes → deactivated water soluble paracetamol glucuronide easily excreted from body AND THERE'S NO DAMAGE TO HEPATOCYTES 2 x 500mg - tiny amount of cytotoxic n-acetyl-p-benzoquinone iminie (NAPBQI) is generated → NAPBQI is rapidly deactivated by hepatic glutathione AND THERE'S NO DAMAGE TO HEPATOCYTES

Question 30

Drug metabolism refers to what?

Answer 30

Drug metabolism refers to the deactivation of pharmacologically active compounds, usually mediated by enzymes.

Question 31

Phase I metabolism often ‘functionalises’ a drug by what?

Answer 31

Phase I metabolism often ‘functionalises’ a drug by adding or exposing a chemically reactive group to facilitate further metabolic enzyme engagement.

Question 32

Phase II metabolism can both?

Answer 32

Phase II metabolism can both render a drug or metabolite inert and add a water-soluble group to facilitate excretion in the urine or the faeces.