reproductive/toxicology Flashcards
What is an adverse drug reaction?
An adverse drug reaction is harmful effect of a drug (try to avoid). It is described by the dose, time course and patient susceptibility
What is a toxic effect?
A toxic effect is an exaggerated therapeutic effect, such as chemotherapy leading to toxic levels.
What is a side effect?
A secondary unwanted effect of a drug (eg. constipation
after taking iron tablets).
How are drugs tested for toxicity before human trials?
Drugs undergo in vitro and in vivo testing to screen for toxicity, often using predictive software like pkCSM.
Define therapeutic window.
The plasma concentration range in which a drug is effective without causing significant toxicity.
What is a therapeutic index?
The ratio of a drug dose required to produce a lethal effect (LD50) divided by the dose required to produce a therapeutic effect (ED50).
Compare a non-chemotherapeutic drug and a chemotherapeutic drug using graphs.
Most drugs need to have a very wide therapeutic window before they are approved for use in humans (eg. TI»_space; 1).
The exception to this rule is drugs that are required to save lives, eg. cancer chemotherapy drugs and drugs used in the treatment of HIV (TI ~ 1)
What is an LD50?
The dose of a compound at which 50% of subjects die
What is an ED50?
The dose of a compound at which 50% of subjects experience a therapeutic effect
What is the maximal tolerance dose (MTD)?
Maximum dose that can be given without leading to
death/lethal effect
What is the non observable effect limit (NOEL)?
The highest level of compound exposure at which no
effect is observed
What is acute toxicity?
Immediate toxic response following a single or short term exposure to a compound
What is chronic toxicity?
A toxic response to long term exposure to a compound.
What is a toxicant?
A man made substance that causes disease or injury (an artificial toxin)
What is a carcinogen?
A compound or other substance that causes cancer.
What is a mutagen?
A compound that causes physical changes in chromosomes or biochemical changes in genes.
What is a tetratogen?
A compound that changes ova, sperm or embryos to increase the risk of birth defects.
What is epigenetic?
Pertaining to non-genetic mechanisms by which compounds cause disease (e.g. environmental factors).
Describe the role of the liver in drug metabolism and the types of liver toxicity that can occur.
The liver metabolizes drugs through uptake by hepatocytes and conversion by cytochrome P450 enzymes, as seen with drugs like paracetamol. Some drugs cleared by the liver, such as methotrexate, are inherently hepatotoxic (intrinsic hepatotoxicity). Liver toxicity can present as cholestasis (impaired bile flow leading to jaundice, e.g., from chlorpromazine) or as immunological reactions (e.g., from halothane). Most liver toxicities manifest as elevated liver enzymes in plasma, which may not require stopping treatment unless severe liver damage occurs.
Describe how drugs are cleared through the kidneys and the potential for kidney toxicity.
Some drugs and their reactive metabolites are cleared predominantly through the urine, concentrating in the renal tubules, which can lead to concentration-dependent toxicity. Non-steroidal anti-inflammatory drugs (NSAIDs) are particularly nephrotoxic, as they cause kidney vasoconstriction and slow the glomerular filtration rate. This exposes kidney cells to higher concentrations of drugs or toxic metabolites over prolonged periods. Any factors that impair kidney function or reduce glomerular filtration rate can enhance the toxic effects of drugs on the kidneys.
Describe how certain drugs can cause neurotoxicity and provide an example.
Some drugs or drug byproducts can cross the blood-brain barrier and cause neurotoxic effects. For example, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a byproduct of heroin synthesis, crosses into the brain and is metabolized by the enzyme MAO-B into the toxic compound MPP+. This metabolite causes irreversible motor defects similar to Parkinson’s disease.
What is haematotoxicity, and how can chronic exposure to certain chemicals lead to blood disorders? Provide an example.
Haematotoxicity refers to toxicity affecting the blood. For instance, chronic exposure to benzene (commonly used in the chemical industry) can lead to blood disorders such as leukemias and anemia. This is due to increased autophagy (cell degradation and reuse) and decreased acetylation in bone marrow mononuclear cells.
What is a Type A ADR?
Type A ADR is a dose-related toxicity that is generally predictable, related to the main pharmacological effect of a drug, and influenced by patient susceptibility. These effects can often be minimized by reducing the dose. Example: High doses of warfarin can cause internal bleeding.
What is a Type B ADR?
Type B ADRs are idiosyncratic, unpredictable adverse reactions often related to immunological responses rather than the drug’s pharmacological actions. They are typically initiated by chemically reactive metabolites and may only occur in certain patients. Example: Paracetamol can cause hypersensitivity reactions in some individuals.
What is a Type C ADR?
Type C ADRs include carcinogenic and teratogenic effects that are dose-dependent and generally predictable. While these reactions are rare with most drugs, they are more common with treatments like cancer chemotherapy drugs.
What are some other ADRs related to overdose and variable pharmacokinetics?
Overdose-related ADRs occur when excessive doses lead to toxic effects unrelated to the intended drug action, as seen with paracetamol hepatotoxicity. Variable pharmacokinetics can also lead to ADRs due to individual differences in drug metabolism, such as those influenced by P450 2D6 polymorphisms.
What are necrosis and apoptosis in the context of cell damage?
Necrosis is uncontrolled cell damage and death, while apoptosis is a controlled, programmed form of cell death mediated by the cell.
How do non-covalent drug interactions contribute to cell damage?
Non-covalent drug interactions do not form physical bonds with targets but can lead to cell damage through mechanisms such as lipid peroxidation, reactive oxygen species (ROS), glutathione (GSH) depletion, and modification of sulfhydryl (-SH) groups.
What are covalent drug interactions, and how do they affect cells?
Covalent interactions involve the formation of physical bonds between drugs and cellular components like DNA or proteins, which can lead to mutagenesis and is a common mechanism in chemotherapy drug toxicity.
What is lipid peroxidation, and how does it involve reactive oxygen species (ROS)?
Lipid peroxidation occurs when reactive drug metabolites or ROS react with cell membrane lipids, leading to membrane damage and increased cell vulnerability.
How does glutathione (GSH) depletion contribute to cell damage?
GSH acts as an antioxidant that protects cells from reactive metabolites. When GSH levels drop to around 30%, cells lose their protective ability and become susceptible to damage.
Why are sulfhydryl (SH) groups important, and how does their modification lead to cell damage?
SH groups are crucial for maintaining protein structure. Reactive drug metabolites can bind to these groups, altering protein function and leading to structural damage.
How does lipid peroxidation lead to cell damage and death?
Lipid peroxidation occurs when reactive drug metabolites or reactive oxygen species (ROS) react with unsaturated lipids, such as phospholipids, in the cell membrane. This initiates a chain reaction, where one damaged lipid leads to the propagation of damage across many lipids. The resulting lipid radicals can react with cell proteins, ultimately causing cell membrane damage and cell death.
How are reactive oxygen species (ROS) generated in drug metabolism, and what impact do they have on cells?
ROS are generated during drug metabolism reactions that require oxygen and involve redox actions. These oxygen radicals, such as superoxide anion (O₂⁻˙), hydroxyl radical (˙OH), hydrogen peroxide (H₂O₂), hydroperoxy radical (HOO˙), and singlet oxygen (O˙), react with nucleic acids, proteins, structural carbohydrates, and lipids, causing cytotoxicity. ROS are highly damaging to cells, leading to effects such as neurodegeneration and excitotoxicity.
What role does glutathione (GSH) play in cell protection, and how does its depletion lead to cell death?
GSH is part of the redox cycle that protects cells from oxidative stress and reactive drug metabolites. Excessive reactive metabolites can deplete GSH faster than it can be regenerated. When GSH levels drop to 20-30% of normal, cells lose their ability to protect against reactive oxygen species (ROS) and other harmful metabolites, leading to cell death from ROS overload.
What is the significance of sulfhydryl (SH) groups in proteins, and how does their modification lead to cell damage?
Free –SH groups are crucial for the catalytic activity of many enzymes, such as cytoskeletal protein actin, GSH reductase, and Ca²⁺-transporting ATPases (which maintain intracellular Ca²⁺ levels). Cysteine, a thiol-containing amino acid, is highly reactive. Reactive drug metabolites can modify these –SH groups, often forming –S-S– crosslinks in an oxidizing environment, which can inactivate the protein and disrupt its function.
What are adverse drug reactions?
Due to interactions between a drug and either another drug or food. Include pharmacodynamic, Chemical, Pharmacokinetic, Metabolic.
What are types of pharmacodynamic drug interactions?
Direct interaction between two or more different drugs (5 classes). Types of pharmacodynamic interactions include additive, synergistic, potentiation, antagonistic, and functional antagonism.
What are chemical drug interactions?
Chemical interactions involve drug-drug complexation or local chemical changes.
What defines a pharmacokinetic drug interaction?
Pharmacokinetic interactions involve competition for similar absorption, distribution, or excretion pathways. Essentially, one drug/substance alters the absorption, distribution or elimination of another drug.
What are metabolic drug interactions?
Metabolic interactions involve changes in drug-metabolizing enzymes. Involves drug metabolising enzymes. Eg. cytochrome P450.
P450’s metabolise a large number of drugs, with different P450’s metabolisong different drugs (whether to activate or inactivate the drug). Some drugs can change the metabolic profile of another drug in the following ways:
* Competitive inhibition of P450’s
* Potent inhibition of P450’s
* Induction of P450’s
What is an additive pharmacodynamic interaction, and can you provide an example?
An additive interaction occurs when two or more drugs with the same effect produce a combined effect equal to the sum of their individual effects (1 + 1 = 2). For example, cyclosporine nephrotoxicity is increased additively by aminoglycoside nephrotoxicity.
What is a synergistic pharmacodynamic interaction, and can you provide an example?
A synergistic interaction occurs when two or more drugs with the same effect produce a combined effect greater than the sum of their individual effects (1 + 1 = 3). For example, the anticoagulant effect of warfarin is significantly increased when combined with aspirin or NSAIDs.
What is potentiation in pharmacodynamic interactions, and can you provide an example?
Potentiation occurs when one drug with no toxic effect at its dose enhances the toxicity of another drug (0 + 1 = 2). For example, isopropanol potentiates the hepatotoxicity of carbon tetrachloride.
What is an antagonistic pharmacodynamic interaction, and can you provide an example?
An antagonistic interaction occurs when the effect of one drug compromises the effect of another drug that has a similar clinical outcome, resulting in a reduced effect (1 + 1 = 0.5). For example, the bactericidal effect of penicillin is inhibited by the bacteriostatic effect of other antibiotics.
What is functional antagonism in pharmacodynamic interactions?
Functional antagonism occurs when two or more substances produce opposite effects, counterbalancing each other, similar to physiological antagonism.
What are chemical drug interactions, and can you provide clinical examples?
Chemical drug interactions occur when a drug binds to another substance or when the chemical environment around the drug is altered. Clinical examples include:
- Tetracycline chelates with metals in antacids and multivitamins, leading to reduced tetracycline absorption.
- Cimetidine increases gastric pH, which reduces absorption of ketoconazole, a drug that is only soluble in a low gastric pH environment.
What is competitive P450 inhibition, and can you provide a clinical example?
Competitive P450 inhibition occurs when two drugs inhibit each other’s metabolism by competing for the same enzyme, leading to increased plasma concentrations of both drugs. The enzyme becomes saturated, unable to metabolize both drugs at maximal capacity.
Clinical Example: Nifedipine and erythromycin both compete for metabolism by hepatic P450 3A4 when co-administered.
What is potent P450 inhibition, and what are its effects on drug metabolism?
Potent P450 inhibition occurs when one drug actively inhibits the function of a P450 enzyme, preventing another drug from being metabolized by that enzyme. As a result, the second drug must be cleared through an alternate route, such as a different metabolic pathway, biliary excretion, or urinary excretion.
Clinical Example: Ketoconazole inhibits P450 3A4, reducing the metabolism of erythromycin, leading to increased erythromycin levels in the blood.
What is P450 enzyme induction, and what effect does it have on drug metabolism?
P450 enzyme induction occurs when one drug increases the expression of a P450 enzyme, which accelerates the metabolism of another drug, resulting in reduced plasma concentrations of the second drug.
Clinical Example: Phenobarbital, an anticonvulsant, upregulates the expression of P450 enzymes like 2B1 and 3A2. This increased expression accelerates the metabolism of drugs such as warfarin, oestrogen, doxycycline, corticosteroids, and other anticoagulants, reducing their plasma levels.
What is interindividual variability, and how does it relate to ADRs?
Interindividual variability refers to differences between individuals that affect drug response. Factors like ethnicity, age, pregnancy, disease, and genetic variations can influence drug metabolism and increase the risk of ADRs if blood concentrations exceed target levels.
How does ethnicity affect drug metabolism?
Ethnic differences in drug-metabolizing enzymes and transporters can impact drug response. For example, Asians often poorly metabolize alcohol due to variations in these enzymes.
How does age impact drug pharmacokinetics?
Age affects drug pharmacokinetics, with significant differences between neonates and the elderly. For instance, reduced renal clearance is common in older adults, affecting drug elimination.
How does pregnancy affect drug pharmacokinetics?
Pregnancy causes large changes in drug pharmacokinetics and immune function. For example, reduced drug metabolism occurs in the fetal compartment.
How can disease impact drug sensitivity and metabolism?
Diseases, especially those affecting the liver and kidneys, can alter plasma protein levels, liver/kidney function, and drug sensitivity, influencing drug response and increasing ADR risk.
How do genetic variations affect drug response?
Genetic differences can alter individual responses to drugs and affect pharmacokinetics, leading to variability in drug efficacy and safety.
What is mutagenesis, and how does it differ from DNA damage?
Mutagenesis refers to changes in DNA that can be replicated, whereas DNA damage is an abnormal alteration in DNA structure that cannot be replicated. Mutations can take the form of microlesions or macrolesions and can be induced by drugs, metabolites, radiation, infectious agents, or environmental agents.
What are some factors that increase the likelihood of DNA mutations?
DNA is most susceptible to change during replication, especially at exposed base pairs like guanine. The risk of mutation is also related to how frequently cells are dividing.
How do drugs cause mutagenesis, and what conditions can result?
Mutagenesis is often caused by covalent modification of DNA, though not always (e.g., methotrexate). Mutations induced by drugs or other agents can lead to carcinogenesis or teratogenesis.
What are DNA microlesions, and how do they affect genetic information?
DNA microlesions are small mutations that occur at the gene level, leading to changes in the amino acid sequence. They include:
1. Base-pair substitution (Point mutation): A single nucleotide change that can alter the amino acid made.
2. Frame-shift mutation: Caused by the addition or deletion of a nucleotide, which shifts the reading frame, altering the downstream amino acid sequence.
Examples:
1. Addition of a nucleotide, such as an “A”, shifts the reading frame, potentially leading to abnormal protein production.
2. Deletion of a nucleotide, like “C”, can introduce a stop codon or drastically change the protein structure.
What are DNA macrolesions, and what types of chromosomal mutations can occur?
DNA macrolesions are large-scale mutations that involve structural changes in chromosomes or changes in chromosome number. Types include:
1. Deletion: Loss of a chromosome segment.
2. Translocation: A segment of one chromosome becomes attached to a non-homologous chromosome.
3. Inversion: A segment of the chromosome is reversed in direction.
4. Duplication: A chromosome segment is repeated.
5. Micronuclei Formation: Damaged chromosome fragments or chromosomes that are not incorporated into the nucleus.
What is carcinogenesis, and what are some key characteristics of chemical carcinogens?
Carcinogenesis is the process by which normal cells transform into cancer cells, with approximately 90% of human cancers attributed to chemicals (such as drugs). Primary chemical carcinogens are highly reactive electrophiles that readily interact with nucleophilic sites like DNA. There are over 100 known human carcinogens, and a long latency period typically exists between exposure and cancer development.
What genetic alterations are involved in carcinogenesis?
Carcinogenesis requires multiple gene mutations and involves alterations that:
- Sustain proliferative signaling (mutation of proto-oncogenes),
- Evade growth suppressors (mutation of tumor suppressor genes),
- Resist cell death,
- Induce angiogenesis,
- Activate invasion and metastasis,
- Reprogram energy metabolism,
- Evade immune destruction.
What is the multistep model of carcinogenesis, and what roles do proto-oncogenes, oncogenes, and tumor suppressor genes play?
The multistep model of carcinogenesis describes the gradual accumulation of mutations leading to cancer, involving key gene types:
- Proto-oncogenes: Genes that help cells grow or stay alive.
- Oncogenes: Mutated proto-oncogenes that have the potential to cause cancer.
- Tumor suppressor genes: Genes that inhibit cell proliferation, helping prevent cancer.
How does feedback regulation work in the menstrual cycle?
Negative Feedback (dominates): Throughout most of the cycle, estrogen and progesterone provide negative feedback to the hypothalamus and pituitary, reducing GnRH, LH, and FSH secretion.
Positive Feedback (mid-cycle): Around ovulation, high levels of estrogen temporarily switch to positive feedback, increasing GnRH and stimulating a surge in LH and FSH, which triggers ovulation.
Inhibin: Secreted by the developing follicle, inhibin specifically inhibits FSH secretion, adding an additional layer of regulation.
