L14 Flashcards
What are the two types of adverse drug reactions (ADRs)?
Type A (dose-dependent), related to the drug’s mode of action (e.g., bleeding with anticoagulants), and Type B (idiosyncratic), unrelated to the drug’s mode of action (e.g., penicillin-induced anaphylaxis).
How does acetaminophen cause hepatotoxicity?
At high doses, acetaminophen is metabolized to a reactive metabolite (NAPQI) by cytochrome P450. NAPQI depletes glutathione, causing oxidative stress and liver cell damage.
What is lipid peroxidation, and how does it contribute to cell damage?
Lipid peroxidation is caused by free radicals attacking membrane phospholipids, forming peroxyradicals that alter membrane permeability and lead to cell death.
What is teratogenesis, and during which developmental stages can it occur?
Teratogenesis refers to fetal malformations due to toxic exposure. It can occur during:
Blastocyst formation: Affects cell division.
Organogenesis (17-60 days): Causes structural defects.
Functional maturation (60 days to term): Impairs growth and hormonal regulation.
How can drugs induce mutagenesis and carcinogenesis?
Drugs can covalently modify DNA bases, leading to mutations during replication. These mutations may cause carcinogenesis, especially in genes regulating cell growth.
What are the key defense mechanisms against oxidative stress in cells?
Glutathione, vitamin E, and other antioxidants neutralize reactive metabolites, preventing oxidative damage to lipids and proteins.
What is the biochemical basis of paracetamol-induced liver failure?
Excess NAPQI depletes glutathione, oxidizes sulfhydryl groups, disrupts calcium ATPases, and increases intracellular calcium, leading to cell death.
What is the mechanism of covalent interactions in drug toxicity?
Reactive metabolites bind covalently to DNA, proteins, or lipids, altering their function and leading to mutagenesis or necrosis.
How do heavy metals like mercury cause toxicity?
Heavy metals covalently bind to sulfhydryl groups in enzymes, disrupting their activity and causing developmental and neurological damage.
What is an example of a teratogenic drug, and what effects does it cause?
Thalidomide caused severe limb malformations (phocomelia) in fetuses when used during pregnancy.
Describe the mechanisms of acetaminophen toxicity and how it leads to liver damage.
Acetaminophen is metabolized to NAPQI by cytochrome P450 enzymes. NAPQI binds to glutathione, depleting stores and leading to oxidative stress. Unbound NAPQI reacts with cellular proteins and lipids, damaging hepatocytes and disrupting calcium homeostasis. This results in liver failure, with symptoms like nausea and vomiting. Alcoholism exacerbates toxicity by increasing P450 enzyme activity.
Discuss the role of oxidative stress in drug-induced cell damage.
Oxidative stress arises when free radicals exceed antioxidant defenses (e.g., glutathione). Lipid peroxidation damages membranes, while protein and DNA modifications disrupt cellular function. For example, acetaminophen-induced oxidative stress damages liver cells, and lipid peroxidation contributes to cell death through altered permeability.
Q: Explain the stages of teratogenesis and how drugs can cause malformations at each stage.
Blastocyst formation: Cytotoxic drugs or ethanol can inhibit cell division, causing embryonic death.
Organogenesis (days 17-60): Drugs like methotrexate disrupt folate metabolism, leading to malformations like spina bifida.
Functional maturation (60 days to term): Hormonal disruptions (e.g., stilbestrol) impair growth and development, increasing cancer risk in offspring.
Compare mutagenesis and carcinogenesis in terms of drug toxicity mechanisms.
Mutagenesis involves DNA base modifications by reactive metabolites, leading to heritable mutations. Carcinogenesis occurs when these mutations affect oncogenes or tumor suppressor genes, resulting in uncontrolled cell growth. For example, pyrimethamine is mutagenic at high doses, while methoxsalen is both mutagenic and carcinogenic.
How are allergic reactions to drugs mediated, and what are the types of hypersensitivity?
Allergic reactions occur when drugs or their metabolites bind to proteins, forming immunogens. Types include:
- Type I (IgE-mediated): E.g., anaphylaxis to penicillin.
- Type II (cytotoxic): Antibodies bind to cell surfaces, leading to destruction.
- Type III (immune complex): Immune complexes deposit in tissues, causing inflammation.
- Type IV (T-cell-mediated): Delayed reactions like contact dermatitis.
