Sesh 6: Metabolism And Excretion

Question 1

Define elimination , metabolism and excretion ?

Answer 1

Elimination - irreversible loss from the body occurs by metabolism and excretion

Metabolism - converts one chemical to another

Excretion - removal of the compound from the body - chemically unchanged or metabolites

Question 2

First pass metabolism.

Answer 2

Gut
Hepatic portal
Liver

Question 3

How do you avoid first pass metabolism ?

Answer 3

Alternative routes of administration, such as, suppository, intravenous, intramuscular, inhalational aerosol, transdermal, or sublingual, avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation.

Question 4

Where does more drug metabolism occur ?

Answer 4

In the liver
Aim of drug metabolism is to make a drug more polar so highly charged and less lipid soluble so can be easily excreted in the urine and not reabsorbed

Question 5

What is a pro drug ?

Answer 5

A prodrug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted.

Question 6

Drugs that undergo first pass metabolism ?

Answer 6

Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, pethidine, tetrahydrocannabinol (THC), ethanol (drinking alcohol), cimetidine, lidocaine, and chlorpromazine.

Question 7

Glucorinidation ?

Answer 7

Glucuronidation, the most common phase II reaction, is the only one that occurs in the liver microsomal enzyme system. Glucuronides are secreted in bile and eliminated in urine. Thus, conjugation makes most drugs more soluble and easily excreted by the kidneys.

Question 8

What is enterohepatic circulation ?

Answer 8

Enterohepatic circulation refers to the process whereby a drug or a metastable metabolite thereof in the liver is secreted into the bile, stored in the gall bladder, and subsequently released into the small intestine, where the drug can be reabsorbed back into circulation and subsequently returned to the liver

Question 9

An example of a drug that undergoes enterohepatic circulation ?

Answer 9

Oral oestrogen contraceptives

In some women the effectiveness of the oestrogen contraceptives may be reduced if they are taking antibiotics at the same time due to the importance of gut bacteria in metabolising the hormone

Question 10

The main enzyme involved in drug metabolism?

Answer 10

The main enzymes involved in metabolism belong to the cytochrome P450 group.

Question 11

Phase 1 metabolism ?

Answer 11

Phase 1 metabolism can involve reduction or hydrolysis of the drug, but the most common biochemical process that occurs is oxidation. (Oxidation is the chemical reaction that occurs when apples turn brown when exposed to the oxygen in air).

Oxidation is catalysed by cytochrome P450 enzymes and results in the loss of electrons from the drug

Question 12

Phase 2 metabolism ?

Answer 12

Phase 2 metabolism involves conjugation - that is, the attachment of an ionised group to the drug. These groups can include glutathione, methyl or acetyl groups. These metabolic processes usually occur in the hepatocyte cytoplasm.

The attachment of an ionised group makes the metabolite more more water soluble. This facilitates excretion

aspirin as example of a drug being metabolised. :

Aspirin undergoes phase 1 hydrolysis to salicylic acid. In phase 2 it is congugated with either glycine or glucoronic acid forming a range of ionised metabolytes that can then be excreted in the urine

Question 13

Drug metabolites ?

Answer 13

Some drugs are administered in an inactive form called a pro-drug, like enalapril. It is the metabolite that is pharmacologically active, (antihypertensive agent.)

Some drug metabolites can be toxic such as those produced from paracetamol. These are usually detoxified by phase 2 conjugation joining with glutathione.

in an overdose situation where the dose of paracetamol is high, there is not enough glutathione to detoxify the metabolites. The metabolites accumulate causing toxicity and can result in hepatitis.
As a solution, compounds are administration to boost the levels of glutathione so that phase 2 metabolism can take place, thus detoxifying the metabolites fully and reducing the risk of liver injury.

Question 14

Factors that impact liver metabolism

Answer 14

Many factors can affect liver metabolism.
In aging the numbers of hepatocytes and enzyme activity declines. Diseases that reduce hepatic blood flow like heart failure or shock can also reduce the metabolic potential of the liver.

Metabolism could also be altered due to a genetic deficiency of a particular enzyme.

For example, Grapefruit juice and the herb St John’s Wort inhibit Cytochrome P450 activity. On the other hand, cigarette smoke and brussel sprouts increase p450 activity

Question 15

What group of medication is aspirin ?

Answer 15

Salicylate belong to NSAIDS

Question 16

Aspirin

Answer 16

Aspirin is also known as acetylsalicylic acid, which is created by a chemical reaction between salicylic acid and acetic acid.

Question 17

Cyp1,2,3 are involved in phase 1 drug metabolism in the liver

Answer 17

X

Question 18

Cyp450 cycle and how drugs are oxidised

Answer 18

So the cyp450 enzyme is complexed with ferric ion (Fe3+) this then combines with the drug

This molecule then combines with an electron. It receives an electron from NADPH -p450 reductase this then reduce the iron to Fe2+

This then combines with an oxygen molecule. It also complexes with a proton and a second electron.

This combines with a proton to yield a water molecule and ferric oxene and DH complex this then extracts hydrogen atom from the drug with the formation of a pair of short lived free radicals

Then liberation from the complex of an oxidised drug

Question 19

What can induce cyp3A4?

Answer 19

St jons wort (used for mild depression)

Question 20

Consequences of cyp induction.

Answer 20

If a CYP enzyme is induced by a compound it may ;
increase the metabolism of a concurrent therapy, or itself (autoinduction)
leading to a reduction in plasma levels
potential decrease in drug efficacy.

Induction of CYP enzymes can also lead to toxicity by increasing reactive metabolite formation.

Question 21

Consequences of inhibition of cyp3A4

Answer 21

The inhibition of CYP3A4 can result in the accumulation of parent drug concentrations that can put the patient at increased risk for side effects and possible toxicity.

Question 22

Phase 2 reactions :

Answer 22

Consist of adding hydrophilic groups to the original molecule , a toxic intermediate that requires further transformation to increase its polarity, these reactions include conjugation, glucuronidation , acetylation and sulfation

Question 23

Phase 1 metabolism ?

Answer 23

Drug + oxygen2 + NADPH —> drug with bound oxygen , H20 + NADPH+

Question 24

Phase 2

Answer 24

So with phase 2 metabolism instead of oxidases they use enzymes called transferases as transferring small polar molecules on the drug to make more water soluble . Oxygen not a requirement in phase 2 like phase 1 metabolism .
Polar molecules include glucuronate, glutathione, sulfate and acetate . So transferring things onto the molecules and this is called conjugation

Question 25

Phase 1 and 2 Of aspirin ?

Answer 25

Phase 1: Aspirin hydrolyses to produce 2 hydro tben oic acid and ethnoic acid

Phase 2: aspirin conjugates glycine or glucuronic acid to make several ionised metabolites that can then be excreted in the urine , for example glycine conjugates using coenzyme A and energy transferred from chemical reactions involving ATP

Question 26

Codeine

Answer 26

Codeine is taken as an analgesic
It is oxidatively demethylayed by cyp2D6 to give morphine.

The majority of pain relief from codeine comes from the glucuronide conjugated metabolite

Question 27

How can heart failure affect drug metabolism ?

Answer 27

Drug clearance may also be diminished due to decreased blood flow to the liver and kidneys, as well as decreased hepatic drug-metabolizing activity.

Question 28

What is the hepatobillary system

Answer 28

The organs of the hepatobiliary system are the liver, gallbladder and bile ducts.

Question 29

What are the main routes if excretion ?

Answer 29

Hepatobillary system - faeces
Kidneys - urine
Lungs - air

sweat, saliva, tears

Question 30

Role of kidneys ?

Answer 30

Maintain electrolyte and water balance
Control ph
Remove waste
Urine output 1500ml a day

Question 31

Substances filtered into the renal tubular include ?

Answer 31

Water
Small proteins
Salts
Glucose
Nitrogenous waste 
Polar drug metabolites

Question 32

How to increase half life of penicillin

Answer 32

To prolong the half life of penicillin prevents it from being rapidly excreted. The drug can be administered with another drug for example probenecid which uses the same transporter preventing the penicillin from being removed so quickly thereby increasing the half life of penicillin

Question 33

Facts

Answer 33

Small unbound drugs are excreted in glomerulus filtration

Lipid soluble and unionised drugs are reabsorbed in the tubules

Weak acids are more rapidly excreted in alkaline urine

Several drugs are removed in kidney only and may cause toxicity in renal impaired patients

Question 34

What does bioavailability mean ?

Answer 34

Fraction of orally administered drug that reaches systemic circulation

Question 35

What is bioavailability affected by ?

Answer 35

Drug preparation
Gut enzymes
Gastric ph
GI motility

Question 36

Any small molecule below 20KDA can defuse across the basement membrane. Anything above is more difficult X the limit for glomerular filtration is 30-60kda

Answer 36

X

Question 37

A lot of drugs bind to plasma proteins so won’t be removed by filtration in the glomerulus such as warfarin it binds to albumin and albumin is 66KDa so then worn pass through plasma membrane

Answer 37

X

Question 38

Where does drug excretioj in kidneys take place

Answer 38

Tubular secretion .

Transporters used are OAT - transports acidic compounds against electrochemical gradient

OCT- transports organic bases along electrochemical gradient

Question 39

Example of a drug that’s transported via OCT?

Answer 39

Penicillin is readily excreted using an organic cation transporter in the tubule unchanged and is one of the reason it has a short half life

Question 40

3 stages of excretion in kidneys ?

Answer 40

There are three main steps: glomerular filtration, reabsorption, and secretion.

Question 41

Elimination half life of a drug ?

Answer 41

This is the time it takes for the concentration of the drug in the plasma to fall by 50% due to elimination.

This gives info about what happens to a drug before reaching its steady state and what will happen after administration

Question 42

Loading dose

Answer 42

If therapeutic effects are needed quickly, and the drug has a long half-life, one can use a loading dose to achieve therapeutic levels on the first dose. The loading dose rapidly achieves the therapeutic response and subsequent doses maintain the response.

Question 43

Penicillin

Answer 43

Penicillin has a short half life of around 1-2 hours due to rapid excretion from kidneys x

Warfarin on the other hand has a long life of around 40 hours

Question 44

What is steady state ?

Answer 44

It’s when the concentration of a drug in the plasma is at a level which has the desired therapeutic effect and is at equilibrium with the amount of drug being eliminated

Question 45

First order kinetics vs zero order kinetics

Answer 45

First order kinetics -
Drugs are metabolised when a small portion of the enzyme active site is occupied

It is a concentration-dependent process (i.e. the higher the concentration, the faster the clearance
Drug does not saturate the enzyme
Drug has a specific half life

Zero order kinetics ;

Most of the enzyme active sites are occupied so a fixed amount of drug is metabolised per unit time

Drug saturates enzymes

Drug has no specific half life

Metabolic rate is maximal and can’t change in proportion to the drug remaining

Question 46

Summary for excretion lecture

Answer 46

Most drugs excreted in urine

Passage through the kidneys can be divided in to glomerular filtration , tubular secretion and reabsorption

Bioavailability, half life and clearance are useful parameters to measure or calculate to compare characteristics of a drug

Elimination is usually by a combination of both first and zero order kinetics depending on whether saturated or not

Question 47

Phase 2 reactions

Answer 47

Glucoronidation 
Sulfoconjugation
Acetylation
Amino acid conjugation
Glutathione S conjugation  
Methylation

Question 48

Glucuronidation ;

Answer 48

Used UDP-glucuronosyltransferases.

40-70% of drugs modified in this way whcih occurs by UDP-hexose to a nucleophillic atom

Question 49

Amino acid conjugation

Answer 49

Amino acid conjugation involves glutamine or glycine addition to a carboxylic acid group –COOH. This is common for metabolism of herbicides, preservatives and products of phase I metabolism

Question 50

Sulfoconjugation

Answer 50

Sulfoconjugation is catalysed by cytosolic sulfotransfereases usually to monocyclic phenols, naphtols etc examples are dopamine, acetaminophen

Question 51

Glutathione s-conjugation

Answer 51

Glutathione s-conjugation occurs by nucleophilic attack on an electrophilic atom c,n or s. Acrolein, found in smoke, is an example substrate

Question 52

Acetylation

Answer 52

Acetylation involves the transfer of an acetyl moiety. N acetyl transferases (NAT1 and NAT2) are expressed in different tissues including liver, bladder, placenta. The population can be classified as fast or slow acetylators, NAT2 is responsible for acetylation of large number of compounds including caffeine.

Question 53

Methylation

Answer 53

Methylation is common phase 2 reaction but minor. It doesn’t affect solubility just the activity of a chemical and is used mainly to deactivate endogenous compounds such as neurotransmitters.

Question 54

Clarithromycin and Simvastatin

Answer 54

Concomitant administration with clarithromycin increases the plasma levels and the risk of myopathy.

Simvastatin — do not prescribe clarithromycin to a person taking simvastatin. If treatment with clarithromycin cannot be avoided, stop treatment with simvastatin temporarily.

Clarithromycin is an inhibitor of the P-450 enzyme system,
Cytochrome P450 enzymes are essential for the metabolism of many medications. .

If too much simvastatin in blood causes liver disease