reproductive/toxicology Flashcards
1
Q
What is an adverse drug reaction?
A
An adverse drug reaction is harmful effect of a drug (try to avoid). It is described by the dose, time course and patient susceptibility
2
Q
What is a toxic effect?
A
A toxic effect is an exaggerated therapeutic effect, such as chemotherapy leading to toxic levels.
3
Q
What is a side effect?
A
A secondary unwanted effect of a drug (eg. constipation
after taking iron tablets).
4
Q
How are drugs tested for toxicity before human trials?
A
Drugs undergo in vitro and in vivo testing to screen for toxicity, often using predictive software like pkCSM.
5
Q
Define therapeutic window.
A
The plasma concentration range in which a drug is effective without causing significant toxicity.
6
Q
What is a therapeutic index?
A
The ratio of a drug dose required to produce a lethal effect (LD50) divided by the dose required to produce a therapeutic effect (ED50).
7
Q
Compare a non-chemotherapeutic drug and a chemotherapeutic drug using graphs.
A
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)
8
Q
What is an LD50?
A
The dose of a compound at which 50% of subjects die
9
Q
What is an ED50?
A
The dose of a compound at which 50% of subjects experience a therapeutic effect
10
Q
What is the maximal tolerance dose (MTD)?
A
Maximum dose that can be given without leading to
death/lethal effect
11
Q
What is the non observable effect limit (NOEL)?
A
The highest level of compound exposure at which no
effect is observed
12
Q
What is acute toxicity?
A
Immediate toxic response following a single or short term exposure to a compound
13
Q
What is chronic toxicity?
A
A toxic response to long term exposure to a compound.
14
Q
What is a toxicant?
A
A man made substance that causes disease or injury (an artificial toxin)
15
Q
What is a carcinogen?
A
A compound or other substance that causes cancer.
16
Q
What is a mutagen?
A
A compound that causes physical changes in chromosomes or biochemical changes in genes.
17
Q
What is a tetratogen?
A
A compound that changes ova, sperm or embryos to increase the risk of birth defects.
18
Q
What is epigenetic?
A
Pertaining to non-genetic mechanisms by which compounds cause disease (e.g. environmental factors).
19
Q
Describe the role of the liver in drug metabolism and the types of liver toxicity that can occur.
A
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.
20
Q
Describe how drugs are cleared through the kidneys and the potential for kidney toxicity.
A
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.
21
Q
Describe how certain drugs can cause neurotoxicity and provide an example.
A
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.
22
Q
What is haematotoxicity, and how can chronic exposure to certain chemicals lead to blood disorders? Provide an example.
A
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.
23
Q
What is a Type A ADR?
A
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.
24
Q
What is a Type B ADR?
A
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.
25
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.
26
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.
27
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.
28
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.
29
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.
30
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.
31
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.
32
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.
33
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.
34
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.
35
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.
36
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.
37
What are adverse drug reactions?
Due to interactions between a drug and either another drug or food. Include pharmacodynamic, Chemical, Pharmacokinetic, Metabolic.
38
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.
39
What are chemical drug interactions?
Chemical interactions involve drug-drug complexation or local chemical changes.
40
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.
41
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
42
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.
43
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.
44
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.
45
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.
46
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.
47
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.
48
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.
49
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.
50
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.
51
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.
52
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.
53
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.
54
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.
55
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.
56
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.
57
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.
58
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.
59
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.
60
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.
61
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.
62
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.
63
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.
64
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.
65
What are the stages in the multistep model of carcinogenesis?
Carcinogenesis involves three main stages:
Initiation: A genetic alteration occurs in a cell. Normally, this damage would be repaired by cellular processes. However, if it is not repaired before replication, it becomes a stable mutation. Cells accumulate mutations over time from multiple sources, with repeated exposures increasing the mutation load, which is why cancer risk increases with age.
Promotion: The initiated cell begins to proliferate, cloning itself to form a mass of modified cells that can be benign or preneoplastic (not yet cancerous).
Progression: The cells undergo further changes, acquiring additional mutations that make them malignant (cancerous). As these cells continue to divide, they become more aggressive and capable of invasion and metastasis.
66
What is a primary carcinogen, and how does it cause cancer?
A primary carcinogen is a chemical that can directly modify DNA, leading to cancer. Example: Alkylating drugs.
67
What is a secondary carcinogen?
A secondary carcinogen requires metabolism or activation to become a carcinogenic product.
68
What is a co-carcinogen, and what is its role in carcinogenesis?
A co-carcinogen is a substance that enhances the effect of a carcinogen, increasing cancer risk. Example: Beta carotene.
69
What is a promoter in the context of carcinogenesis, and how does it function?
A promoter enhances tumorigenicity when administered after a carcinogen, affecting the rate of cell division, terminal differentiation, or death of tumor precursor cells. Example: Estrogen.
70
What is teratogenesis, and how does sensitivity to teratogens vary during development?
Teratogenesis is the process by which developmental abnormalities occur due to exposure to toxicants, particularly during critical periods of organ formation (organogenesis) in the embryonic period. The sensitivity to teratogens varies by developmental stage:
Weeks 0-2: The embryo is usually not susceptible to teratogens, and exposure to toxicants more often leads to death rather than malformations.
Weeks 3-8 (Embryonic period): This is the period of greatest sensitivity, where teratogens can cause structural malformations in organs like the heart, limbs, eyes, and brain.
Weeks 9-38 (Fetal period): While structural malformations are less likely, drugs that interfere with nutrient supply or hormone levels can cause functional deficits and growth retardation.
71
What are some known teratogens and their specific effects on fetal development?
Androgenic chemicals: Can cause virilization, esophageal, and cardiac defects.
Radioiodine: Leads to bone defects.
Anticancer drugs (e.g., Cyclophosphamide): Associated with multiple defects and increased risk of death.
Warfarin: Causes nasal hypoplasia and various central nervous system (CNS) disorders.
Ethanol: Leads to fetal alcohol syndrome.
Thalidomide: Causes impaired brain development.
72
What are the general mechanisms of teratogenicity?
Teratogenic mechanisms are not clearly understood, but teratogens can bind to DNA, proteins, or lipids, affecting cell function and development.
73
What are bioactivation-dependent teratogens?
Bioactivation-dependent teratogens require metabolism to electrophilic metabolites to exert their teratogenic effects.
74
What are non-bioactive dependent teratogens, and how do they work?
Non-bioactive dependent teratogens do not require biotransformation and directly disrupt cell differentiation. Example: Accutane (isotretinoin) causes apoptosis and cell cycle arrest, critical during neural development.
75
How do anticonvulsant agents like phenytoin act as teratogens?
Phenytoin, used by epileptic mothers, doubles the risk of birth defects, likely due to a P450-generated epoxide metabolite.
76
How do cytotoxic chemotherapy drugs cause teratogenic effects?
Cytotoxic drugs target rapidly dividing cells, causing direct DNA conjugation or altering DNA/nucleotide synthesis or replication.
77
What is the teratogenic effect of thalidomide?
Thalidomide is known for causing severe birth defects, although its specific mechanism of teratogenicity is complex and not entirely understood.
78
What is fetal alcohol syndrome (FAS), and what are its main characteristics?
FAS is the most common non-genetic cause of mental retardation, associated with increased risks of miscarriage, stillbirth, premature birth, and low birth weight. It is characterized by:
- Impaired neurological development and function,
- Social and behavioral problems,
- Abnormal growth and physical deformities (e.g., limb abnormalities),
- Slow growth after birth,
- Characteristic facial features,
- Vision and hearing problems,
- Kidney, heart, and bone defects.
79
What is GnRH, where is it produced, and what does it do?
GnRH is produced in the hypothalamus (brain) and stimulates the secretion of FSH (follicle-stimulating hormone) and LH (luteinizing hormone) by the anterior pituitary gland.
80
What is FSH, where is it produced, and what is its function?
FSH is produced in the anterior pituitary (brain) and stimulates the maturation of follicles in the ovaries.
81
What is LH, where is it produced, and what role does it play in the reproductive cycle?
LH is produced in the anterior pituitary (brain). It stimulates the release of the ovum from the mature graafian follicle and the conversion of the remaining follicle into the corpus luteum.
82
What is estrogen, where is it primarily produced, and what are its main functions?
Estrogen is the major female hormone, primarily produced by ovarian follicles. It builds the endometrium and generally exerts negative feedback on GnRH, LH, and FSH secretion, reducing their levels. However, during mid-cycle (ovulation), estrogen provides positive feedback, increasing GnRH and FSH secretion.
83
What is progesterone, where is it produced, and what is its main function?
Progesterone is produced by ovarian follicles and helps stabilize the endometrium, facilitating implantation of a fertilized ovum. High levels of progesterone exert negative feedback on the hypothalamus, reducing GnRH and mainly LH secretion to prevent ovulation.
84
What is inhibin, and what is its role in the reproductive cycle?
Inhibin is a hormone that specifically inhibits FSH secretion.
85
Describe the process by which GnRH regulates the production of LH and FSH.
1. GnRH neurons reside in the hypothalamus.
2. These neurons have terminal projections in the median eminence (ME).
3. GnRH is released from the nerve terminals in the ME.
4. It travels through the hypothalamic-hypophyseal portal system (a blood pathway) to the anterior pituitary.
5. GnRH stimulates the production of LH and FSH by gonadotroph cells in the anterior pituitary.
86
What happens in the follicular phase of the menstrual cycle?
1. Low levels of estrogen stimulate FSH release through negative feedback.
2. FSH promotes the maturation of multiple primary follicles.
3. Only the dominant follicle, which secretes the most estrogen, develops into the Graafian follicle (containing the ovum).
4. Secondary and mature follicles increase plasma estrogen levels.
5. High estrogen levels mid-cycle stimulate LH release through positive feedback.
6. LH surge causes the Graafian follicle to rupture, releasing the ovum.
87
What occurs during the luteal phase of the menstrual cycle?
1. The ruptured follicle transforms into the corpus luteum, which secretes progesterone and estrogen.
2. If the ovum is not fertilized, progesterone and estrogen secretion ceases, leading to the shedding of the endometrium (menstruation).
88
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.
89
How are sex hormones produced in the follicles, and what roles do theca and granulosa cells play?
Theca Cells: Stimulated by LH to take up cholesterol and synthesize androgens. The pathway is as follows: Cholesterol → Pregnenolone → Androstenedione → Testosterone.
Granulosa Cells: Stimulated by FSH to convert androgens into estradiol via the enzyme aromatase. Androstenedione from theca cells is converted to estradiol within granulosa cells.
Final Product: Estradiol (a form of estrogen) is then released into the blood and follicular fluid.
90
What are the key changes that occur during menopause?
1. Cessation of menstruation (~50 yo)
2. Run out of follicles (sort of)
3. No follicles released
4. Reduced oestrogen and progesterone levels in plasma (only small amounts of oestrogen and progesterone are synthesised in other organs)
5. No development of the endometrial lining and no menstruation
91
Why do hot flushes occur during menopause?
During menopause, the reduction in estrogen levels leads to the loss of estrogen-mediated inhibition of GnRH and FSH release. This hormonal change contributes to the occurrence of hot flushes.
During menopause, the reduction in estrogen levels leads to the loss of estrogen-mediated inhibition of GnRH and FSH release. This hormonal change contributes to the occurrence of hot flushes.
92
What hormonal changes occur during menopause, and how do they affect the body?
1. Fail to recruit follicles by FSH
2. Reduced estrogen, little progesterone & inhibin
3. Negative feedback on hypothalamus and pituitary
4. Increased GnRH (causes hot flushes) and
5. Increased FSH and LH (due to lack of overriding negative feedback)
93
What are the broader effects of low estrogen and progesterone levels in the body during menopause?
Estrogen receptors (ERα and ERβ) are located throughout the body, including in the brain, bones, fat, cardiovascular system, and immune cells. Low endogenous levels of estrogen and progesterone during menopause can lead to:
- Headaches,
- Mood disturbances and depression,
- Fragile bones and bone pain (e.g., sore back),
- Increased risk of cardiovascular disease,
- Changes in immune function,
- Vaginal dryness,
- Thinning/dull hair,
- Weight gain,
- Loss of muscle tone,
- Loose teeth, and more.
94
What are the different methods of hormone delivery, and what are they used for?
- Tablets
- Nasal spray
- IUD (Intrauterine device)
- Vaginal ring/pessary
- Subcutaneous implants
- Patches (safer for women with a risk of blood clotting)
- Vaginal cream
- Vaginal tablet
- Vaginal preparations: Provide localized relief of symptoms like vaginal dryness and incontinence.
95
What are the two types of contraceptive pills?
1. Combined estrogen and progestin pill.
2. Progestin-only pill.
96
Why should estrogens not be given without progestins to women with a uterus?
In the absence of progestins, estrogens cause hyperproliferation of the endometrium, increasing the risk of endometrial cancer. This is not a concern for post-hysterectomy women.
97
How does natural estrogen compare to modified estrogens in potency and absorption?
Natural estrogen is more potent than modified forms but is poorly absorbed from the gut and is rapidly cleared from the body.
98
What was the issue with the original high-estrogen combined pill, and what is the "magic number" for estrogen dose?
The original combined pill used a high estrogen dose (150-50 µg), which was associated with a high incidence of side effects. The "magic number" for estrogen dose is 20 µg, which is effective with fewer side effects. Doses below 20 µg may not provide sufficient contraceptive effect.
99
What is the difference between high progesterone and High estrogen?
High estrogen causes very fluid cervical fluid, enhancing sperm penetration. High progesterone thicken cervical fluid, blocking sperm penetration.
100
Why choose to take the progestin only pill
over the combined pill?
Women who have contraindications to taking oestrogen
* History of hypertension
* History or stroke
* History of thromboembolism (DVT)
BUT the progestin only pill is not recommended for women with a history of clots!!!
101
What is the purpose of estrogen replacement in hormone therapy for menopause?
Estrogen replacement artificially increases plasma estrogen levels, providing negative feedback on the hypothalamus and pituitary to reduce GnRH, FSH, and LH levels, which helps alleviate hot flushes. It also replaces lost estrogen, maintaining normal function in cells with estrogen receptors.
102
What role does progestin play in hormone replacement therapy for menopause?
Progestin replacement increases plasma progesterone levels, mimicking the luteal phase. It provides negative feedback on the hypothalamus, reducing GnRH secretion, which helps stop hot flushes. Progestin generally has positive effects on cells with progesterone receptors but does not affect plasma estrogen levels or cells with estrogen receptors.
103
How does levonorgestrel work?
Dose: Levonorgestrel is given at 1.5 mg (compared to 0.15 mg in regular contraceptives).
Timing: Must be taken within 3-5 days (most effective within 3 days with an 85% reduction in conception).
Mechanism: Prevents the LH surge, which delays or prevents ovulation. Only effective if taken 2 days before the LH surge.
Effects: Does not affect ovum fertilization, implantation, or the fetus.
Side Effects: Menstrual irregularities, nausea, and vomiting (if vomiting occurs within a few hours, a second pill may be needed).
104
How does ulipristal work as an emergency contraceptive, and what are its key details?
Dose: Ulipristal is given at 30 mg and does not need to be taken with food.
Timing: Must be taken within 3-5 days (most effective within 3 days with an 85% reduction in conception).
Mechanism: Inhibits progesterone binding to its receptor, preventing or delaying ovulation (exact mechanism is unknown).
Effects: Its effect on an implanted fertilized egg is unknown.
Side Effects: Primarily menstrual irregularities, with nausea and vomiting being less common than for levonorgestrel.
105
What about deliberately inhibiting
hormone production or action? Why would you want to do this?
1. Pregnancy termination
2. Treatment of Oestrogen receptor (ER) positive or ‘overexpressing’ breast cancers
106
How does mifepristone (RU486) work in pregnancy termination?
Mechanism: Mifepristone is a competitive inhibitor of the progesterone receptor with a two-fold higher affinity than progesterone itself.
Dosage: The process starts with a 200 mg tablet of mifepristone.
Action: Causes the breakdown of the decidua (the uterine lining), which is essential for pregnancy maintenance.
Follow-up: A prostaglandin pill is taken afterward to induce uterine contractions, completing the termination.
107
How are oestrogens made?
1) Cholesterol is converted to progesterones (influence of LH)
2) Progesterones are converted to androgens (LH)
3) Androgens are converted to oestrogens (via aromatase UNDER influence of FSH)
108
How do oestrogens work?
1. Oestrogen enters the cell by passive diffusion
2. Binds to the oestrogen receptor (ER)
3. Conformational change in the receptor
4. Dimerizes with another oestrogen-bound ER
5. Enters the nucleus
6. Binds to the oestrogen responsive element (ERE)
on DNA
7. Conformational change allows binding of
coactivators
8. Binding of coactivators promotes gene
transcription
109
How do aromatase inhibitors like letrozole and anastrozole work, and what is their effect on estrogen synthesis?
Aromatase inhibitors, such as letrozole and anastrozole, work by competitively blocking androgen binding to the active site of the aromatase enzyme (P450 aromatase). This prevents the conversion of androgens (androstenedione and testosterone) into estrogens (estrone and estradiol), thereby reducing estrogen levels.
110
How does tamoxifen inhibit the estrogen receptor, and what effect does it have on gene transcription?
1. Tamoxifen is metabolised to several ‘active’ forms
(eg. 4-hydroxy tamoxifen) by liver CYP2D6 & 3A4
2. 4-OH-Tam enters the cell
3. Competitively binds to the oestrogen receptor
(ER)
4. NO conformational change in the receptor
5. Dimerizes with another 4-OH-Tam bound ER
6. Enters the nucleus
7. Binds to the oestrogen responsive element (ERE)
on DNA
8. Lack of conformational change prevents binding
of coactivators
9. No gene transcription
111
What maintains the flaccid state of the penis?
The sympathetic nervous system keeps smooth muscle in the corpus cavernosa and blood vessels (arterioles) contracted. This maintains bidirectional blood flow, preventing blood retention in the corpus cavernosa.
112
What changes occur in the erect state of the penis?
During sexual stimulation, neurotransmitters are released from cavernous nerve terminals, leading to smooth muscle relaxation. This allows more blood to flow into the corpus cavernosa and compresses the veins, preventing blood from escaping, resulting in an erection.
113
What role does the brain play in initiating an erection?
The brain is essential for initiating an erection. If there is no interest or stimulation from visual, smell, imaginary, or touch stimuli, the erection process will not proceed.
114
What are the two main stimulation pathways involved in initiating an erection?
1. NANC (Nonadrenergic/Noncholinergic) Nerve Pathway: Stimulates Ca²⁺ influx, leading to nitric oxide (NO) production, which relaxes smooth muscle.
2. Cholinergic Nerve Pathway: Acetylcholine (Ach) is released, activating muscarinic receptors on endothelial cells, which in turn release NO.
115
What is the inhibition pathway that leads to detumescence (loss of erection)?
The adrenergic nerve releases noradrenaline (NA), causing smooth muscle contraction, which leads to detumescence.
116
How does the NO pathway contribute to smooth muscle relaxation?
1. Nitric oxide (NO) activates guanylate cyclase, which converts GTP to cGMP.
2. cGMP activates protein kinase G (PKG).
3. PKG phosphorylates certain proteins, leading to:
- Opening of K⁺ channels and closing of Ca²⁺ channels, sequestering Ca²⁺ back into the sarcoplasmic reticulum (SR).
- Reduction of intracellular Ca²⁺.
- Smooth muscle relaxation.
117
How does the prostaglandin (PGE1) pathway lead to smooth muscle relaxation?
1. PGE1 binds to its G protein-coupled receptor on corpus cavernosum smooth muscle cells.
2. This activates adenylate cyclase.
3. Adenylate cyclase converts ATP to cAMP.
4. cAMP activates protein kinase A (PKA).
5. PKA phosphorylates certain proteins, leading to smooth muscle relaxation.
118
What is PGE1 (alprostadil), and how is it used for erectile dysfunction?
PGE1 (alprostadil) is an injectable drug for erectile dysfunction with an efficiency of approximately 70-90%, typically taking effect within 10 minutes. It is injected directly into the corpus cavernosa.
119
What is required before using alprostadil injections for erectile dysfunction?
Several training sessions with a healthcare provider are required to learn proper injection techniques for administering alprostadil into the corpus cavernosa.
120
What are the potential side effects of alprostadil (PGE1) injections for erectile dysfunction?
Possible side effects include:
- Pain at the injection site,
- Painful prolonged erection (priapism) lasting more than 8 hours,
- Redness or lumps,
- Rash or itching,
- Trouble urinating,
- Feeling faint,
- Potential permanent damage to the penis or fibrosis.
121
What is papaverine, and how does it work as an injectable for erectile dysfunction?
Usage: Papaverine is less commonly used and is primarily prescribed if alprostadil is contraindicated.
Mechanism: The exact mechanism is not completely understood, but it is proposed to inhibit phosphodiesterase 5, leading to vasodilation.
Side Effect: Does not induce localized pain.
122
How does phentolamine work as an injectable for erectile dysfunction, and in what scenarios is it used?
Mechanism: Phentolamine causes vasodilation through competitive antagonism of α1 adrenoceptors.
Combination Use: Often used in combination with papaverine and/or alprostadil (formulated as Trimix, which is also available in gel form).
Formulation and Dosage: Trimix must be compounded by a pharmacist and used within 1-6 months. Effective for >90% of cases, with doses ranging from 50 to 200 µL, increased in 25 µL increments as needed.
Prescription Criteria: Typically prescribed when single-dose therapy has failed.
123
What are PDE5 inhibitors, and how do they work for erectile dysfunction?
PDE5 inhibitors, such as sildenafil (Viagra), vardenafil, and tadalafil, inhibit the hydrolysis of cGMP, allowing cGMP to remain longer in the smooth muscle cells. This leads to increased cGMP activity and prolonged smooth muscle relaxation, facilitating an erection.
124
When should PDE5 inhibitors be taken for optimal effectiveness?
They should be taken 1-2 hours before intercourse to allow time to reach maximum concentration (tmax) in the blood. Food can delay the onset of some PDE5 inhibitors like sildenafil.
125
How effective are PDE5 inhibitors, and are there any prerequisites for their action?
PDE5 inhibitors are about 70% effective in healthy patients. They require stimulation from nonadrenergic/noncholinergic (NANC) nerves for activation and eventual muscle relaxation.
126
How are PDE5 inhibitors metabolized in the body?
They are eventually metabolized and inactivated by liver enzyme P450 3A4.
127
What visual disturbances can PDE5 inhibitors cause, and in which patients should they be avoided?
PDE5 inhibitors can cause a "blue aura" due to cross-binding to PDE6 in the retina. They should be avoided in patients with hereditary degenerative retinal disorders or with vision loss in one eye.
128
How do PDE5 inhibitors cause headaches and dizziness, and are migraines or seizures common?
Headaches and dizziness are dose-related side effects, though migraines and seizures are rare.
129
What skin-related side effects are associated with PDE5 inhibitors?
Skin flushing and itching can occur as side effects of PDE5 inhibitors.
130
What gastrointestinal side effect is commonly associated with PDE5 inhibitors?
Indigestion is a common gastrointestinal side effect of PDE5 inhibitors.
131
Why should patients with unstable angina be cautious when using PDE5 inhibitors?
Sexual activity is equivalent to mild to moderate exercise, so patients with unstable angina may need an exercise or stress test before using PDE5 inhibitors.
132
What uncommon urinary side effect can occur with PDE5 inhibitors?
Some patients may experience bladder pain.
133
How does diabetes affect the effectiveness of ED drugs?
Diabetes can cause endothelial dysfunction, increased contractile sensitivity, reduced nitric oxide (NO) signaling, and diabetic neuropathy, all of which can impair ED drug effectiveness.
134
Why might vascular problems (veno-occlusive disorders) render ED drugs ineffective?
Vascular problems prevent adequate blood vessel dilation, making drug intervention ineffective.
135
How does hypogonadism affect the response to ED drugs?
Hypogonadal patients have reduced testosterone, which is essential for regulating nitric oxide synthase (NOS) and PDE5, impacting ED drug effectiveness.
136
Why does prostate removal impact the effectiveness of ED drugs?
Prostate removal surgery can damage the penile nerve bundle, disrupt brain signaling, or damage the entire organ, affecting ED drug efficacy.
137
How does smoking impact ED drug effectiveness?
Smoking negatively affects blood vessels and blood flow, which can reduce the efficacy of ED drugs.
138
How does smoking impact erectile function and blood flow in the penis?
Smoking damages endothelial cells, causing them to release vasoconstrictors, which harden blood vessels and reduce penile blood flow.
139
What harmful radicals are formed due to smoking, and how do they affect nitric oxide synthase (NOS)?
Smoking generates superoxide and peroxynitrite radicals, which decrease NOS activity, crucial for erectile function.
140
Can smoking cessation reverse these effects?
Smoking cessation can help overcome these issues if the individual has not been a lifelong smoker, allowing for potential recovery of endothelial and erectile function.
141
What is the anatomical location and structure of the prostate?
The prostate is a doughnut-shaped structure located just below the bladder and in front of the rectum, surrounding the proximal end of the urethra. It typically measures 20-30 cm³ and consists of glandular, connective, and smooth muscle tissue.
142
What is the primary function of the prostate?
The prostate secretes a milky fluid that makes up about 25% of semen volume. This fluid contains citrate, which supports ATP production for sperm, and enzymes like prostate-specific antigen (PSA) that liquefy coagulated semen.
143
What is Benign Prostatic Hyperplasia (BPH)?
BPH is a chronic, common disorder in men characterized by the enlargement of the prostate due to nodular prostatic remodeling, inflammation, and an increase in cell number and size in the prostate's transition zone. It affects 50% of men over 50 and 90% of men over 80.
144
What causes BPH?
BPH is stimulated by androgens, which promote hyperplasia (increase in cell numbers) and hypertrophy (increase in cell size) in the prostate.
145
What are the symptoms of BPH?
Symptoms include abdominal pain, difficulty urinating and slow urine flow, incontinence due to pressure on the bladder, feeling of urinary urgency, and pain that can worsen in cold conditions or when stressed. BPH is often asymptomatic in early stages.
146
When does BPH typically become symptomatic?
BPH is generally asymptomatic when the prostate is less than 30 cm³. Beyond this size, symptoms may appear, and treatment may be necessary.
147
What is the primary cause of BPH at the cellular level?
BPH is an androgen-dependent process caused by high local concentrations of 5α-dihydrotestosterone (DHT), a potent testosterone metabolite.
148
How is DHT produced, and why is it significant?
DHT is produced by the enzyme 5α-reductase (5AR). It plays a key role in promoting prostate development, growth, and differentiation, binding to testosterone receptors with higher affinity and for a longer duration than testosterone.
149
How does DHT relate to male-patterned balding?
High local levels of 5AR in the scalp convert testosterone to DHT, which is associated with male-patterned balding.
150
How does BPH pathogenesis occur?
BPH pathogenesis is linked to chronic inflammatory reactions induced by the growing prostate stromal cells.
151
What are treatments for BPH?
Goal: Return normal urinary function.
Approach 1:
5α-Reductase (5AR) Inhibitors
Mechanism: Inhibits 5AR enzyme to decrease DHT levels and reduce prostate size.
Approach 2:
α1 Adrenergic Antagonists
Mechanism: Inhibits prostate smooth muscle contraction to alleviate urinary obstruction.
Final Straw:
Surgical Removal of Prostate
Used when other treatments fail to relieve symptoms.
152
What is the goal of 5AR Inhibitors (the 'sterides')?
Inhibit 5α-Reductase (5AR) to decrease plasma DHT.
Aim to reduce prostate size and relieve pressure on bladder and urethra.
153
What is Finasteride and what are its uses?
Used to treat androgenic alopecia.
Recommended for men with prostate size >30 cm³.
Treatment Duration: 6 months.
Plasma Half-life: ~8 hours.
154
What is Dutasteride and what are its uses?
Has a longer plasma half-life (~5 days) than finasteride.
Provides more consistent results.
Often preferred over finasteride for better efficacy.
155
What are the side effects of 5AR inhibitors?
1. Erectile dysfunction (ED), ejaculation problems, and reduced libido.
2. Male breast enlargement.
3. Potential increase in male breast cancer risk—monitor breast tissue changes.
156
What is the primary aim of using α1 adrenergic antagonists in BPH treatment?
The aim is to reduce the degree of smooth muscle contraction in the prostate, thereby decreasing pressure on the urethra and improving urinary flow. This is especially beneficial when 5AR inhibitors cannot be tolerated or are contraindicated.
157
Why are α1 adrenergic antagonists specific for α1 receptors and what is the advantage?
These antagonists specifically target α1 receptors (not α2 receptors in the heart), which prevents association with presynaptic α2 receptors and avoids causing tachycardia.
158
What is the indication and receptor selectivity of Alfuzosin and Tamsulosin?
Alfuzosin and Tamsulosin are indicated only for BPH. They are α1A-selective, targeting the capsule of the prostate gland and bladder neck. This selectivity leads to fewer cardiac side effects as they have minimal effect on α2 and α1 receptors.
159
How effective are Alfuzosin and Tamsulosin in treating BPH compared to other α1 adrenergic antagonists?
Alfuzosin and Tamsulosin are less effective in treating BPH than Prazosin and Terazosin; however, they have a lower risk of causing hypotension due to their receptor specificity.
160
What are the uses and selectivity characteristics of Prazosin and Terazosin?
Prazosin and Terazosin have less receptor selectivity than Alfuzosin and Tamsulosin. They are more effective in BPH treatment but require dose titration to minimize hypotensive effects. Additionally, they can be used as third-line drugs for hypertension.
161
What are the common side effects associated with α1 adrenergic antagonists?
Common side effects include hypotension, dizziness, fatigue, floppy iris syndrome (a complication during cataract surgery), nasal congestion, and first-dose hypotension.
162
What are the rare side effects that may occur with α1 adrenergic antagonists?
Rare side effects include vision disturbances, tachycardia, and palpitations.
