Sesh 6: Metabolism And Excretion Flashcards
Define elimination , metabolism and excretion ?
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
First pass metabolism.
Gut
Hepatic portal
Liver
How do you avoid first pass metabolism ?
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.
Where does more drug metabolism occur ?
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
What is a pro drug ?
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.
Drugs that undergo first pass metabolism ?
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.
Glucorinidation ?
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.
What is enterohepatic circulation ?
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
An example of a drug that undergoes enterohepatic circulation ?
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
The main enzyme involved in drug metabolism?
The main enzymes involved in metabolism belong to the cytochrome P450 group.
Phase 1 metabolism ?
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
Phase 2 metabolism ?
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
Drug metabolites ?
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.
Factors that impact liver metabolism
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
What group of medication is aspirin ?
Salicylate belong to NSAIDS
Aspirin
Aspirin is also known as acetylsalicylic acid, which is created by a chemical reaction between salicylic acid and acetic acid.
Cyp1,2,3 are involved in phase 1 drug metabolism in the liver
X
Cyp450 cycle and how drugs are oxidised
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
What can induce cyp3A4?
St jons wort (used for mild depression)
Consequences of cyp induction.
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.
Consequences of inhibition of cyp3A4
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.
Phase 2 reactions :
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
Phase 1 metabolism ?
Drug + oxygen2 + NADPH —> drug with bound oxygen , H20 + NADPH+
Phase 2
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
Phase 1 and 2 Of aspirin ?
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
Codeine
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
How can heart failure affect drug metabolism ?
Drug clearance may also be diminished due to decreased blood flow to the liver and kidneys, as well as decreased hepatic drug-metabolizing activity.
What is the hepatobillary system
The organs of the hepatobiliary system are the liver, gallbladder and bile ducts.
What are the main routes if excretion ?
Hepatobillary system - faeces
Kidneys - urine
Lungs - air
sweat, saliva, tears
Role of kidneys ?
Maintain electrolyte and water balance
Control ph
Remove waste
Urine output 1500ml a day
Substances filtered into the renal tubular include ?
Water Small proteins Salts Glucose Nitrogenous waste Polar drug metabolites
How to increase half life of penicillin
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
Facts
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
What does bioavailability mean ?
Fraction of orally administered drug that reaches systemic circulation
What is bioavailability affected by ?
Drug preparation
Gut enzymes
Gastric ph
GI motility
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
X
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
X
Where does drug excretioj in kidneys take place
Tubular secretion .
Transporters used are OAT - transports acidic compounds against electrochemical gradient
OCT- transports organic bases along electrochemical gradient
Example of a drug that’s transported via OCT?
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
3 stages of excretion in kidneys ?
There are three main steps: glomerular filtration, reabsorption, and secretion.
Elimination half life of a drug ?
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
Loading dose
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.
Penicillin
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
What is steady state ?
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
First order kinetics vs zero order kinetics
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
Summary for excretion lecture
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
Phase 2 reactions
Glucoronidation Sulfoconjugation Acetylation Amino acid conjugation Glutathione S conjugation Methylation
Glucuronidation ;
Used UDP-glucuronosyltransferases.
40-70% of drugs modified in this way whcih occurs by UDP-hexose to a nucleophillic atom
Amino acid conjugation
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
Sulfoconjugation
Sulfoconjugation is catalysed by cytosolic sulfotransfereases usually to monocyclic phenols, naphtols etc examples are dopamine, acetaminophen
Glutathione s-conjugation
Glutathione s-conjugation occurs by nucleophilic attack on an electrophilic atom c,n or s. Acrolein, found in smoke, is an example substrate
Acetylation
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.
Methylation
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.
Clarithromycin and Simvastatin
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
