week 21 p2 Flashcards
Why do drugs
(or any other chemical)
cause toxicity? Reason 1: ADME-driven toxicity
- Chemical can disrupt ADME processes
- (e.g. disruption of phase I and II enzymes).
- I this disruption alters the pharmacokinetic profile of the chemical
- (e.g. leading to a higher-than usual concentration in the body, and therefore increasing the risk of toxicity).
Effect of drugs on CYP450s (a example ofADME-driven
- CYP450s can be inhibited or induced by chemicals. Inhibition of CYPs can lead to unwanted drug–drug interactions due to the resulting large variations of drug concentrations between patients.
- The poor metabolization of the drug can result in higher-then-usual concentrations, increasing the risk trigger toxicological effects.
- CYP450-mediated effects are particularly important to determine the risk of drug combinations (and cocktails of non-pharma chemicals
- CYP enzymes can increase ROS and alter the redox balance, creating oxidative stress, through their catalytic cycle and contribute to disease development.
- However, some substrates, modified by CYP enzymes to create reactive intermediates or products, can also contribute to disease development. Such as hyperopic lung injury, ROS mediated hepatotxity( veith, et al, 2017)
Effects of drugs that causes ADME-driven (Example: Statins + CYP3A4 Inhibitors)
• Statins- lower the level of low-density lipoprotein (LDL) cholesterol in the blood.
High-dose statin monotherapy can lead to rhabdomyolysis (risk:1/10,000 people)
What can toxicity of CYP3A54 inhibitor and statins cause
• Rhabdomyolysis is a serious syndrome due to a direct or indirect muscle injury.
• It results from the death of muscle fibres and release of their contents into the bloodstream.
This can lead to serious complications such as renal failure.
Issues with Example: Statins + CYP3A4 Inhibitors
• Some statins are particularly susceptible to drug-drug interaction dynamics (e.g. simvastatin and lovastatin).
• The risk of rhabdomyolysis is increased with concomitant use of certain drugs
Potent inhibitors of CYP34A can significantly increase the serum concentrations of the active forms of simvastatin, lovastatin, and atorvastatin.
What are the drugs most likely to interact with statins include:
• fibrates (especially gemfibrozil)
• azole antifungal agents,
• Amiodarone
• macrolides (especially erythromycin and clarithromycin, but not azithromycin)
• protease inhibitors
calcium-channel blockers (especially verapamil and diltiazem)
Effects of drugs that causes ADME-drive Example: Omeprazol + Clopidogrel
• Omeprazole – Proton pump inhibitor (e.g. used in the treatment of gastroesophageal reflux disease, peptic ulcer disease, to prevent upper gastrointestinal bleeding in people who are at high risk)
• Omeprazole, a CYP2C19 inhibitor, decreases the antiplatelet activity of clopidogrel by inhibiting the biotransformation of the clopidogrel pro drug into its active metabolite.
• Clopidogrel - is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk.
CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. Clopidogrel is a prodrug, which is activated in two steps, first by CYP2C19
Another example of ADME-mediated toxicity: is disruption of drug distribution
• Two drugs may compete for the same albumin binding site.
• According to their affinity to the binding site, one drug may displace the other causing an increase in the free concentration of the displaced drug.
This increase in free concentration may increase the risk of developing adverse effects, as it results in an increase of drug concentration at the target site.
example of ADME-mediated toxicity: is disruption of drug distribution
• the administration of aspirin to a patient treated chronically with warfarin results in displacement of the latter from its binding site.
the increase in plasma concentration of free warfarin causes the development of serious haemorrhagic reactions.
Another reason that causes toxity is Reason 2: Bioactivation
• The metabolic transformation of the chemical leads to a novel chemical species that is toxic.- bioactivation.
most important metabolic systems involved in bioactivation reactions are CYP450 and peroxidase enzymes, producing either electrophilic or radical metabolites.
The process of Bioactivation
• Xenobiotic , nontoxic metabolite, reactive metabolites
• Bids to cellular binding
Results in toxity and cellular repair
What is reactive metabolites: Electrophiles
Reactive metabolites are usually electron deficient molecules and are referred to as electrophiles (molecules containing positive centres).
They are typically either positively charged or have a partial positive charge (δ+).
What is the process of reactive metabolites : Electrophiles
• If not detoxified properly, electrophiles can react with electron rich species, i.e. nucleophiles (molecules containing negative centres),
• through covalent bond formation.
• The nucleophiles usually contain atoms such as S, N, or O that have a lone pair of electrons,
• which can form a new bond to the electrophile.
Such nucleophiles are present on macromolecules such as proteins, nucleic acids and lipids.
How does electrophiles work
• Electrophiles act as acceptors of electrons in a reaction.
• By accepting some electrons from nucleophiles, electrophiles will “quench” their positive or partial positive charge
making a more overall stable species.
How Effects of reactive metabolites: Electrophiles
- Chemically reactive metabolites can directly react with proteins
- causing changes in protein structure or protein folding.
- These modified proteins are processed by antigen presenting cells
- and can look “foreign” to the immune system leading to an immune response.
- Chemically reactive electrophiles can also covalently react with nucleic acids on the DNA
- thereby causing changes in DNA structure or gene expression.
- Changes in DNA can lead to mutagenicity, teratogenicity or carcinogenicity.
What is Types of reactive metabolites : Free radicals
Free radical refers to compounds having an unpaired electron
How does free radicals happen
• Since electrons need to be paired to form a chemical bond, a free radical cannot react covalently with nucleophiles. Rather they:
• react with another free radical to form a covalent bond
• abstract a hydrogen atom from a neutral molecule to generate a new radical
abstract an electron to form an anion and generate a radical cation
What are the biological effects of reactive metabolites
• Toxicity may accrue through formation of a chemically reactive metabolites, which, if not detoxified,
• can cause the modification of biological macromolecules.
As a result of their high reactivity, reactive metabolites are often considered to be short-lived. This is not always true, however, because reactive intermediates can be transported from one tissue to another, where they may exert their deleterious effects.(Attia 2010)
What is Effects of reactive metabolites: quinones
• Cause different toxicological effects in vivo including acute cytotoxicity, immunotoxicity, genotoxicity and carcinogenesis.
• Can cause cellular damage through alkylation of crucial cellular proteins and/or DNA.
• Quinones are also highly redox active molecules, which can redox cycle with their semiquinone radicals leading to formation of ROS including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical.
Production of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromolecules, including lipids, proteins, and DNA .
What is the examples of toxicity involving quinones
• Benzene-induced leukemia
Remoxipride-induced aplastic anemia
What Is the consideration of paracentamol
• can trigger severe liver toxicity in human patients at high doses
• The major portion of paracetamol is conjugated with either sulfate or glucuronic acid to form water-soluble metabolites
• and only small amounts of the reactive intermediate, believed to be N-acetyl-p-benzoquinonimine (NAPQI), are formed by the cytochrome P450 enzymes.
• When therapeutic doses of paracetamol are ingested, the small amount of reactive intermediate forms is efficiently deactivated by conjugation with the antioxidant glutathione (GSH).
What happens where there is large amount of paracetamol ingested
• the sulphate and glucuronide cofactors (PAPS and UDPGA) become depleted, resulting in more of the paracetamol being metabolized to the reactive intermediate.
• As long as GSH is available, most of the reactive intermediate can be detoxified. When the concentration of GSH in the liver also becomes depleted,
• NAPQI covalently bind to sulfhydryl (-SH) groups of various cellular proteins increases, resulting in hepatic necrosis.
• If sufficiently large amounts of paracetamol are ingested, as in drug overdoses and suicide attempts, extensive liver damage and death may result.
