Pharmacology and the Liver

Question 1

Define metabolism:

What is elimination?

Answer 1

• the process by which the tissue enzymes, principally in the liver, catalyse the conversion of a frequently lipid soluble drug to an often less active and more polar form that is more readily excreted from the body

Elimination is the linked processes of metabolism and excretion

Question 2

Answer 2

Question 3

Explain MEC and MTC:

What is the therapeutic window?

Answer 3

MEC - minimum effective concentration

MTC - maximum tolerated concentration

For a drug to achieve an effect, it must reach a critical concentration in the plasma (MEC) but must be well below the MTC which causes significant unwanted effects.

Therapeutic window is the range of doses which can effectively treat disease without causing toxic effects, the larger the therapeutic window, the safer the drug.

Question 4

What is the therapeutic ratio/index:

Label the graphs showing which drug is ‘safe’ and ‘unsafe’:

Does a safe drug have a high or low ratio?

Give examples of safe and unsafe drugs:

Answer 4

TR = MTC/MEC

A ‘safe’ drug has a high ratio, such as penicillins and benzodiazepines, whereas ‘unsafe’ drugs have a low ratio, like cardiac glycosides and barbiturates

Question 5

Define steady state:

What is Cl?

What is the relationship between steady state plasma concentration and infusion rate for drugs that exhibit first order kinetics?

How is C_ss determined and when is it reached?

Answer 5

At steady state (ss): rate of drug administration = rate of drug elimination

Clearance (Cl) is the sum of all clearance processes: Cl_(renal) + Cl_(hepatic) + Cl_(other)

For drugs that exhibit first order kinetics, the steady state plasma concentration is linearly related to the infusion rate.

C_ss is determined by half-life, and not the infusion rate. C_ss is reached after approx 5 half-lives

Question 6

What is a loading dose?

What is its aim?

Answer 6

A loading dose is an initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose.

The aim is to get a patient to reach steady state quicker.

Question 7

What is the main organ involved in drug metabolism and what is the name of this metabolism? Name the other organs which can have metablic activity

What is First Pass Metabolism?

Answer 7

• Liver: hepatic metabolism is the main organ, however GI tract and lungs do have metabolic activity
• Drugs given orally are usually absorbed in the small intestine and enter the portal system to travel to the liver, where they may be extensively metabolised

Question 8

What are the two important effects of drug metabolism?

Are there any exceptions?

Answer 8

• Drug is made more hydrophilic - accelerates its excretion by the kidneys
• Metabolites are usually less active than parent drug
• Some metabolites can be as active or more active than parent drug e.g. Diazepam metabolised to two active drugs
• Prodrugs are inactive until metabolised in the body to active drug e.g. levodopa metabolised to active dopamine

Question 9

Explain phase 1 reaction of the liver:

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Answer 9

• Involve biotransformation of a drug to a more polar metabolite by introducing or unmasking a functional group e.g. -OH, -SH, -NH₂
• Oxidations are most common reactions - catalysed by an important class of enzymes, the mixed function oxidases (cytochrome P450) with low substrate specificity

Question 10

Explain phase 2 reaction of the liver:

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Answer 10

Drugs/metabolites whicha re not polar enough to be excreted by the kidneys quickly;

• usually occur in liver and involve conjugation of a drug or its phase 1 metabolite with an endogenous substance
• resulting conjugates are almost always less active and polar molecules readily excreted by kidneys