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Flashcards in Hepatic drug metabolism Deck (20)
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What are the 4 phases of pharmacolokinetics



What is first pass metabolism?

After absorption, orally-administered drugs enter portal system​. Drugs can be rapidly metabolised by multitude of enzymes in liver.​
Thus levels reaching systemic circulation can be greatly reduced​
i.e. has a major effect on bioavailability ​

A drug may pass through the liver many times because of continual systemic blood circulation.​
Each time a drug passes through the liver, a fraction of it is metabolised.​
Molecules of metabolized drugs are excreted out of the body either via the kidneys or through the bile.​


What happens in phase I metabolism?


Provide a functional group (e.g. OH or NH2) to:​
increase polarity of the drug​
provide a site for phase II reactions​

For many drugs, decreases pharmacological activity of drug. (N.B. for pro-drugs, increases pharmacological activity.)


What is the mixed function oxidase system?

The cytochrome P450 enzyme requires the presence of molecular oxygen, NADPH and NADPH cytochrome P450 reductase in order to function. This combination of factors is referred to as the mixed function oxidase system.


What are the major cytochrome P450 isoforms?



What are phase II reactions?

Drug molecules that possess a suitable site that was either present before phase I or is the result of a phase I reaction, are susceptible to phase II reactions.​

Phase II reactions involve conjugation - the attachment of a large chemical group to a functional group on the drug molecule.​

The resulting conjugate is almost always pharmacologically inactive and is more hydrophilic and thus more easily excreted from the body.​


What chemical groups are often involved in conjugation?

Glucuronyl, acetyl, methyl, sulphate and glutathione


What is phase III transport?

Conjugated metabolite is moved for excretion.

Into the circulation (for renal elimination) - most common route. ​

Into bile (for elimination in faeces/ enterohepatic circulation) - principal route for larger molecules (>500 Da).​


How are drugs metabolised by neonates?

- Hepatic drug-metabolizing enzyme systems are immature.​
- N.B. renal clearance is also inefficient.​
- Lower doses of all drugs are needed.


How are drugs metabolised by children?

- Metabolic clearance can be quicker in children than in adults (because CYPs are mature and the relative liver mass and hepatic blood flow are higher).​
- Dosages of medicines should be obtained from a paediatric dosage handbook.​
- Prescribed dosages are judged by considering both age and body surface area.


How are drugs metabolised by older adults?

- Overall capacity for hepatic drug metabolism, particularly phase I reactions, is reduced (because the relative liver mass and hepatic blood flow are lower).​
- Simultaneous use of several drugs is common.​
- It is usual to start drug treatment with the smallest effective dose.​
- Rational prescribing should seek to minimize the number of drugs used.​


What happens in CYP450 enzyme induction?

- Long-term administration of drugs often induces CYP450 activity by enhancing the rate of synthesis or reducing the rate of degradation of the CYP enzyme(s).​
- CYP450 enzyme induction results in more rapid metabolism of the drug and all other drugs metabolised by the same CYP450 enzyme(s).​
- Plasma levels and biological effects of the drugs decrease.​
- A lack of therapeutic efficacy can result.
N.B. Except for pro-drugs, whose biological effects will increase.​


What does St John's Wort do?

- A “herbal remedy” commonly taken for depression. ​
- Available over-the-counter.​
- Induces activity of many P450 enzymes including CYP3A4, CYP2C9, CYP2E1 and CYP1A2.​
- Increases the metabolism, and therefore reduces the plasma concentration, and potentially the therapeutic efficacy, of drugs such as warfarin, antiepileptics, oral contraceptives.


What happens in CYP450 enzyme inhibition?

- Drugs and other substances can inhibit CYP450 activity.​
- CYP450 enzyme inhibition results in reduced metabolism of other drugs metabolised by this CYP450 enzyme(s).​
- Plasma levels and biological effects of the drug(s) increase.​
- Potentially toxic drug levels and adverse effects can result.
N.B. Except for pro-drugs, whose biological effects will decrease.


What does cimetidine do?

- A histamine H2-receptor antagonist. ​
- A broad, but relatively weak, inhibitor of many CYP450 enzymes.​ (therefore ranitidine is prescribed instead of this)
- Reduces the metabolism of endogenous steroids and co-administered drugs such as warfarin, phenytoin and quinidine.​
- Plasma levels of these drugs will therefore be elevated and biological effects increased.​
- Potentially toxic drug levels and adverse effects can result.


Why do poor metabolisers (PM) nor ultra-rapid metabolisers (URM) respond well to codeine?

Poor Metaboliser:
Cannot convert codeine to morphine
No pain relief
Exaggerated side-effects of codeine, especially is if dose is increased in futile attempt to relieve pain

Ultra-rapid metaboliser:
Ultra-rapid conversion of codeine to morphine
Toxic levels of morphine
Opioid toxicity


What are the side effects of codeine?

Nausea and vomiting​


What are the symptoms of opioid toxicity?

Respiratory depression​
Skeletal muscle flaccidity​
Cold and clammy skin​


What are the effects of liver disease on drug action?

In cirrhosis:​
- decreased drug-metabolising capacity.​
- Hypoproteinaemia.​
- Porto-systemic shunting directs drugs away from the liver.

Impact on drug action:​
Increased bioavailability resulting from impaired first-pass metabolism.​
Decreased plasma protein binding of drugs.


Define bioavailability

The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action