Week 8 part 1 - Toxicology & teratogenesis Flashcards

Question

Lipid peroxidation (& reactive oxygen species)

Answer 1

Reactive drug metabolites or oxygen species react with lipids in cell membranes and damage the membrane * Reactive drug metabolites (or reactive oxygen species) can react with unsaturated lipids (like phospholipids) on the cell membrane * Once one reactive drug metabolite attacks a membrane lipid, the process propagates to damage many lipids * Cell death results from damage to the cell membrane or from the product of reactions between lipid radicals and cell proteins

Answer 2

GSH is an antioxidant that protects cells. When it becomes depleted to ~30%, cells cannot protect themselves against reactive metabolites * GSH redox cycle protects cells from oxidative stress and reactive drug metabolites * Excessive amounts of reactive drug metabolites can use up cellular GSH too rapidly for it to be sufficiently regenerated --> depleted GSH * When cellular GSH falls to 20-30% of normal levels, cells cannot protect themselves against ROS and reactive drug metabolites, so the cell dies as a result of ROS overload.

Answer 3

SH groups are important for maintaining the functional structure of proteins. Reactive drug metabolites can bind to these and damage the protein structure * Free –SH groups have an important role in the catalytic activity of many enzymes (targets include cytoskeletal protein actin, GSH reductase and Ca+2 transporting ATPases – maintain intracellular Ca levels) * Cysteine is a highly reactive amino acid that contains thiols * Reactive drug metabolites can react with these –SH groups (for instance, to form –S-S- crosslinks) by creating an oxidising environment and inactivate the protein

Answer 4

* Drug metabolism reactions that require O2 involve redox actions that cause oxygen radicals to be produced * These ROS react with nucleic acids, proteins, structural carbohydrates and lipids and are highly cytotoxic (kill cells) * Superoxide anion (O2-˙) * Hydroxyl radical (˙OH) * Hydrogen peroxide (H2O2) * Hydroperoxy radical (HOO˙) * Singlet oxygen (O˙) * Cause neurodegeneration and excitotoxicity

Answer 5

Pharmacodynamic * Additive, synergistic, potentiation, antagonistic, functional antagonism Chemical * Drug-drug complexation or local chemical changes Pharmacokinetic * Competition for similar absorption, distribution or excretion pathways Metabolic * Changes in drug metabolising enzymes

Answer 6

Additive * If 2 or more drugs have the same pharmacodynamic effect, the effect of both drugs given at the same time is added together (ie. 1 + 1 = 2) * Eg. magnitude of cyclosporine nephrotoxicity is increased ‘additively’ by aminoglycoside nephrotoxicity Synergistic * If 2 or more drugs have the same pharmacodynamic effect, the effect of both drugs given at the same time is greater than the added effect of both drugs (ie. 1 + 1 = 3) * Eg. Blood anticoagulant effect of warfarin is dramatically increased in magnitude if given together with aspirin or NSAIDS (warning label on warfarin tablets) Potentiation * If one drug with no toxicological effect at the dose given is given with another drug that DOES exhibit toxicity, the magnitude of the toxic drug is increased (ie. 0 + 1 = 2) * Isopropanol potentiates the hepatotoxicity of carbon tetrachloride Antagonistic * If the pharmacodynamic effect of 1 drug COMPROMISES the pharmacodynamic effect of another drug which should have the same ultimate clinical outcome (ie. 1 + 1 = 0.5) * Bacteriocidal effects of penicillin on bacteria are inhibited by the bacteriostatic effect of other antibiotics (eg. bacteriostatic = stop growth, bacteriocidal = rely on cell growth to kill cells) Functional antagonism * Two or more substances produce the opposite effect to each other, counterbalancing each other (identical to physiological antagonism).

Answer 7

Altered drug absorption or receptor binding - Drug binds to another substance - Chemical environment around a drug is altered Clinical examples: Tetracycline chelates metals in antacids and multivitamins --> Reduced tetracycline absorption Cimetidine increases gastric pH --> Ketoconazole is only soluble at low gastric pH --> Coadministration of ketoconazole with cimetidine decreases ketoconazole absorption

Answer 8

Essentially, one drug/substance alters the absorption, distribution or elimination of another drug. (ADME) Eg. Grapefruit and many drugs

Answer 9

* Involves drug metabolising enzymes. Eg. cytochrome P450 * P450’s metabolise a large number of drugs * Different P450’s metabolise 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

Answer 10

* When 2 drugs that have been administered competitively inhibit each others metabolism --> increase plasma concentrations of both drugs * Ie. The enzyme can only work at a maximal capacity, so it becomes saturated by the drugs Clinical example: Co-administration of nifedipine and erythromycin Both are metabolised by hepatic P450 3A4 and compete with each other for metabolism

Answer 11

* One drug actively inhibits a P450 from working, preventing another drug from being metabolised by that P450 * Means that the second drug needs to be cleared via an alternate route (different metabolic pathway, biliary excretion, urinary excretion etc) Clinical example: ketoconazole on erythromycin (??)

Answer 12

One drug INCREASES the level of expression of a P450 that is required to metabolise another drug -> accelerated metabolism of the second drug --> reduced plasma concentrations Clinical example: Phenobarbital is used as an anticonvulsant…. But also upregulates the expression of lots of P450s (like 2B1 & 3A2) But….lots of other drugs are metabolised by these P450s …. Eg. oestrogen, doxycycline, corticosteroids, anticoagulants….

Answer 13

Anything that increases blood concentrations of a drug above ‘target’ levels can cause ADRs ‘Interindividual variability’ Ethnicity * Differences in drug metabolising enzymes and transporters * Eg. Asians poorly metabolise alcohol Age * Neonatal vs old age – differences in drug pharmacokinetics * Eg. reduced renal clearance with increased age Pregnancy * Large changes in drug pharmacokinetics and immune function * Eg. reduced drug metabolism in the ‘foetal compartment’ Disease * Particularly diseases affecting the liver and kidneys * Changes in plasma proteins, liver/kidney function or sensitivity to drugs Genetic variations * Changes in response to various drugs or pharmacokinetics

Answer 14

Drug (or metabolite/radiation/infectious agent/environmental agent) induced changes to DNA can cause carcinogenesis or teratogenesis Often caused by covalent modification of DNA, but not always (e.g. methotrexate) * DNA damage is distinct from mutagenesis: - DNA damage = abnormal alteration in DNA structure that cannot be replicated. - Mutation = replacement of a gene in DNA that can be replicated - Mutations can be in the form of microlesions or macrolesions. * DNA is most susceptible to change when in the process of replication - Expose base pairs, particularly guanine - Risk is related to how frequently cells are dividing

Answer 15

Change a single base nucleotide to change the amino acid made Addition or deletion of a nucleotide to change the amino acid sequence

Answer 16

Include: 1. Change in the number of chromosomes 2. Structural changes in chromosomes * Deletion: loss of chromosome segment * Translocation: segment of one chromosome becomes attached to a non homologous chromosome * Inversion: A change in direction of the nucleotide code * Duplication: repetition of a chromosome segment 3. Micronuclei formed (damaged chromosome fragments or chromosomes not incorporated into the nucleus)

Answer 17

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. * Approx 90% of human cancers are caused by chemicals (ie drugs) * All ‘primary’ chemical carcinogens are highly reactive electrophiles that react readily with nucleophilic sites in the cells (e.g. DNA) * >100 known human carcinogens * Long latency between carcinogen exposure and cancer development * Carcinogenesis involves more than a single gene mutation (need many targeted mutations). Include genetic alterations involved in: - Sustaining proliferative signalling (mutation of proto-oncogenes) - Evading growth suppressors (mutation of tumour suppressor genes) - Resisting cell death - Inducing angiogenesis - Activating invasion and metastasis - Reprogramming energy metabolism - Evading immune destruction

Answer 18

Genes that helps cells grow or stay alive.

Answer 19

Proto-oncogenes that have mutated, giving it the potential to cause cancer

Answer 20

Genes that inhibit cell proliferation

Answer 21

Initiation: genetic alteration of a cell * Normally repaired by cellular processes * If NOT repaired before the cell replicates, it becomes a stable biological lesion * Cells accumulate mutations from multiple sources over time (age related cancers) * Repeated exposure is usually required to increase the number of mutations Promotion: initiated cell clones itself (proliferates) to form a mass of modified cells that can be either benign or preneoplastic (NOT cancerous) Progression: cells undergo additional changes to make them malignant (cancerous). E.g. as cells divide they acquire addition mutations that make the cell more aggressive.

Answer 22

Primary Carcinogen: Chemical that can directly modify DNA (e.g. alkylating drugs) Secondary carcinogen: Requires metabolism/activation to a carcinogenic product Co-carcinogen: Enhances the effect of a carcinogen (e.g. beta carotene) Promoter: Enhances tumorigenicity(carcinogenicity) when given after a carcinogen (e.g. estrogen; affect the rate of cell division, terminal differentiation or death of tumour precursor cells)

Answer 23

the process where exposure to harmful agents during pregnancy causes structural or functional abnormalities in the developing fetus, resulting in congenital birth defects or malformations.

Answer 24

an agent or factor which causes malformation of an embryo e.g. Thalidomide - R enantiomer: sedative - S enantiomer: teratogenic

Answer 25

Not clearly understood mechanisms! Teratogens can bind to DNA, proteins or lipids Bioactivation-dependent teratogens: * requires metabolism to electrophilic metabolites Non-bioactive dependent teratogens: * do not require biotransformation * disrupt cell differentiation directly (known mechanisms) * E.g. Accutane (isotretinoin) causes apoptosis and cell cycle arrest (critical during neural development) after a single dose Anticonvulsant agents (phenytoin): * risk of birth defects in offspring of treated epileptic mums is 2x * believed to involve a P450 generated epoxide metabolite Cytotoxic chemotherapy drugs (cyclophosphamide): * anticancer drugs target rapidly dividing cells * direct DNA conjugation or alter DNA/nucleotide synthesis or replication Thalidomide

Answer 26

Introduced in 1957 as a hypnotic and sedative drug * Recommended for use in pregnancy * Prescribed to treat morning sickness * Subject to toxicity testing in mice only (resistant to thalidomide teratogenicity) * Evidence of teratogenicity first noticed in 1961 **(withdrawn)**

Answer 27

* Most common non-genetic cause of mental retardation * Increased risk of miscarriage, stillbirth, premature birth, low birth weight * Characterised by: * Impaired neurological development and function * Social and behavioural problems * Abnormal growth and physical deformities (e.g. limbs) * Slow growth after birth * Characteristic facial features * Vision and hearing problems * Kidney, heart and bone defects