Flashcards
What is pharmacology?
The study of medicines and drugs, including their action, use, and effects on living systems.
What are the two main branches of pharmacology?
- Pharmacodynamics – The study of how drugs affect the body.
- Pharmacokinetics – The study of how drugs move through the body.
What is a therapeutic drug?
A drug that manages symptoms but does not necessarily cure the underlying cause (e.g., diuretics for hypertension, insulin for diabetes).
What is a curative drug?
A drug that eliminates the underlying physiological cause of a condition (e.g., antibiotics, antifungals, some anti-cancer agents).
What are the three types of drug names?
- Generic name – Official name (e.g., ibuprofen, paracetamol).
- Brand name – Commercial name (e.g., Nurofen®, Panadol®).
- Chemical name – Scientific molecular structure (e.g., (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid).
Which drug name should always be used in medical and academic writing?
The generic name.
What are the main biological targets for drug action?
- Proteins (most common)
- Receptors
- Enzymes
- Ion channels
- Transport proteins
- Lipids (e.g., lipoproteins targeted in viral infections)
- Nucleic acids (e.g., anticancer agents targeting DNA/RNA)
What is an agonist?
A molecule that binds to and activates a receptor, triggering a biological response.
What is an antagonist?
A molecule that binds to a receptor but does not activate it, blocking the action of an agonist.
What is affinity?
The strength of attraction between a drug and its receptor.
What is efficacy?
The ability of a drug to produce a biological effect after binding.
What are some examples of drugs and their targets?
- Salbutamol – β2 agonist (used for asthma).
- Atenolol – β1 antagonist (used for hypertension).
- Nifedipine – Calcium channel blocker (used for hypertension).
- Benzodiazepines – GABA receptor modulators (used for anxiety/sleep disorders).
What are ion channel receptors?
Channels that open or close in response to drugs, affecting ion movement (e.g., Nifedipine for calcium channels).
What are G protein-coupled receptors (GPCRs)?
Receptors that activate intracellular signaling when drugs bind (e.g., Phenylephrine – α1 agonist, Propranolol – β antagonist).
What are enzyme-linked receptors?
Receptors activated by ligands that trigger intracellular enzymatic responses (e.g., insulin receptors).
What are nuclear receptors?
Intracellular receptors that regulate gene expression when bound by drugs (e.g., steroid hormones, glitazones like rosiglitazone).
What are examples of drugs acting on enzymes?
- Captopril – ACE inhibitor (used for hypertension).
- Fluorouracil – Anticancer drug replacing uracil in DNA synthesis.
- L-Dopa – Precursor converted to dopamine in Parkinson’s disease.
- SSRIs (Selective Serotonin Reuptake Inhibitors) – Block serotonin reuptake, treating depression.
- Lithium (Li⁺) – Mood stabilizer used in bipolar disorder.
What is Emax?
The maximum response a drug can produce.
What is EC50?
The concentration of a drug needed to achieve 50% of the maximal response.
What is ED50?
The dose of a drug required to achieve 50% of the maximal response.
What is Kd (dissociation constant)?
The concentration of drug at which 50% of receptors are occupied.
What is a competitive antagonist?
A drug that competes with the agonist for the same binding site and can be reversed by increasing agonist concentration.
What is a non-competitive antagonist?
A drug that binds to a different site on the receptor and reduces its response, cannot be reversed by increasing agonist concentration.
What is an irreversible antagonist?
A drug that binds permanently to a receptor, blocking agonist activity indefinitely.
What is allosteric modulation?
When a drug binds to a site other than the active site to enhance or inhibit receptor function.
What is an allosteric activator?
A drug that enhances the effect of an agonist.
What is an allosteric inhibitor?
A drug that reduces the effect of an agonist.
What is a partial agonist?
A drug that partially activates a receptor but does not produce the full effect of a full agonist.
What is an inverse agonist?
A drug that binds to a receptor but produces an opposite effect to an agonist.
What is a neutral antagonist?
A drug that blocks the activity of both agonists and inverse agonists but has no effect on its own.
What key concepts should you understand from pharmacology?
- What a drug is.
- The definitions of affinity and efficacy.
- Major drug targets.
- How to identify Emax and EC50 from a concentration-response curve.
- The difference between competitive and non-competitive antagonism.
- The types of allosteric modulation.
What is physiology?
Physiology is the study of the normal functions of living organisms and their parts.
What is pathophysiology?
Pathophysiology is the study of the functional changes associated with or resulting from disease or injury.
What is a drug target?
A drug target is a molecule in the body, usually a protein, that is intrinsically associated with a particular disease process and that could be addressed by a drug to produce a desired therapeutic effect.
What is affinity?
Affinity is the tendency of a drug to bind to its target.
What is efficacy?
Efficacy is the ability of a drug to produce a maximum response when it binds to its target.
What is a reversible drug?
A reversible drug binds to its target and then dissociates, allowing the target to return to its original state.
What is an irreversible drug?
An irreversible drug binds permanently to its target, usually through a covalent bond, and the effect of the drug lasts until the target is replaced by the body.
What is an agonist?
An agonist is a drug that binds to a receptor and activates it, producing a biological response. It has both affinity and efficacy.
What is a partial agonist?
A partial agonist is a drug that binds to a receptor and activates it, but produces a submaximal response even at full occupancy. It has affinity and partial efficacy.
What is an inverse agonist?
An inverse agonist is a drug that binds to a receptor and reduces its activity, producing an effect opposite to that of an agonist. It has affinity and negative efficacy.
What is an antagonist?
An antagonist is a drug that binds to a receptor and blocks its activation by agonists, preventing a biological response. It has affinity but no efficacy.
What is Kd?
Kd is the dissociation constant, a measure of the affinity of a drug for its target. The lower the Kd, the higher the affinity.
What is selectivity?
Selectivity is the ability of a drug to preferentially bind to one target over another. A drug is more selective for a target if it has a lower Kd for that target compared to other targets.
What is Bmax?
Bmax is the maximum amount of drug that can bind to a target. Bmax refers to the maximum number of binding sites available for a ligand on a receptor in a given system
What type of graph is used to measure efficacy?
A dose-response curve is used to measure efficacy.
What is the measurement used to compare the efficacies of drugs at a target?
EC50 is the concentration of a drug that produces 50% of its maximum response.
What biological molecules can be drug targets?
Proteins, DNA, RNA, and lipids can be drug targets.
What are the different types of proteins that can be drug targets?
Receptors, enzymes, ion channels, and transporters can be drug targets.
What is the main link between cancer cells and infectious agents discussed in this lecture?
Both cancer cells and infectious agents (e.g. bacteria) replicate rapidly from a single cell, expanding to form large populations. This rapid proliferation makes timely treatment crucial to prevent further spread or metastasis in cancer, and high bacterial load in infections.
What are the key similarities in how cancer cells and infectious agents pose treatment challenges?
- Rapid replication: They both multiply quickly if left untreated.
- Host cell similarity: Many basic processes (e.g., DNA replication) in cancer cells are similar to normal cells, making selective targeting difficult.
- Timeliness: Delaying treatment allows cells or microbes to proliferate, complicating treatment.
In the cell cycle, during which phase does DNA replication occur?
DNA replication takes place during the S phase (Synthesis phase) of the cell cycle.
When do transcription and translation take place in the cell cycle?
Transcription and translation occur continuously throughout interphase (G1, S, and G2) and can also happen (to a lesser degree) in M phase. Essentially, cells still need to produce proteins almost all the time.
What happens in the M phase of the cell cycle?
M phase (mitosis) is when the cell divides, producing two daughter cells. This includes nuclear division (mitosis) and cytoplasmic division (cytokinesis).
What are the key features of ‘encapsulated’ versus ‘invasive’ (metastatic) tumors?
- Encapsulated Tumors: Confined in one location, often with a clear boundary. They can sometimes be surgically removed and treated more easily.
- Invasive/Metastatic Tumors: Spread outside their original “capsule,” moving into surrounding tissues or distant organs, making them harder to treat.
What role do proto-oncogenes and tumor suppressor genes play in cancer development?
- Proto-oncogenes normally encourage healthy cell growth; if mutated/overactive, they become oncogenes that drive uncontrolled proliferation.
- Tumor suppressor genes normally act like “brakes” to slow or stop cell division; if these are inactivated or lost, cells can proliferate unchecked.
What is apoptosis and why is it significant in both healthy cells and cancer therapy?
Apoptosis is programmed cell death, a controlled way for the body to remove damaged or unwanted cells. In healthy tissue, it prevents the accumulation of defective cells. Many cancer therapies work by triggering apoptosis in cancer cells that have DNA damage.
What is the difference between the extrinsic and intrinsic apoptosis pathways?
- Extrinsic Pathway: Triggered by external “death signals” (e.g., FasL binding to Fas receptor), activating caspases to dismantle the cell.
- Intrinsic Pathway: Triggered internally (often via DNA damage leading to p53 activation), causing mitochondrial pore formation and release of cytochrome c, which activates caspases.
How does p53 help initiate apoptosis in response to DNA damage?
When DNA is damaged, p53 becomes phosphorylated and active. It can upregulate pro-apoptotic proteins (e.g., Bax, Bad) that form pores in mitochondria, releasing cytochrome c and driving the cell down the intrinsic apoptosis pathway.
Why do pharmacologists focus on targeting DNA synthesis or replication in cancer cells?
Cancer cells rely heavily on constant DNA replication to expand. Drugs that interfere with DNA polymerases, nucleotide production, or DNA structure can specifically impair rapidly dividing cells, slowing or stopping tumor growth.
What are the defining properties of bacteria that make them good targets for antibiotics?
- Cell wall: Absent in human (eukaryotic) cells, a major target for beta-lactam antibiotics.
- Different enzymes and structures: Such as DNA gyrase for DNA supercoiling and unique ribosomal subunits.
How do β-lactam antibiotics (like penicillins and cephalosporins) work against bacteria?
They inhibit the transpeptidase (often called penicillin-binding proteins) that cross-links peptidoglycan layers in the bacterial cell wall. This weakens the cell wall, causing bacterial cell lysis (bactericidal effect).
What is the difference between “bactericidal” and “bacteriostatic” antibiotics?
- Bactericidal: Kills bacteria outright (e.g., β-lactams).
- Bacteriostatic: Inhibits bacterial growth or replication without directly killing, relying on the host’s immune system to clear the microbes (e.g., sulfonamides).
How do sulfonamides and trimethoprim block bacterial nucleic acid synthesis?
- Sulfonamides: Inhibit the enzyme (dihydropteroate synthase) converting p-aminobenzoic acid (PABA) into dihydropteroic acid, a folate precursor.
- Trimethoprim: Inhibits bacterial dihydrofolate reductase, blocking the formation of tetrahydrofolate needed to synthesize thymidine nucleotides.
Why is trimethoprim more selective for bacteria than human cells?
It binds bacterial dihydrofolate reductase approximately a thousand times more strongly than the human enzyme, thus preferentially blocking folate synthesis in bacteria.
What is the role of DNA gyrase in bacteria and how do gyrase inhibitors work?
DNA gyrase introduces negative supercoils into bacterial DNA, essential for replication. Gyrase inhibitors (e.g., nalidixic acid) disrupt this process, preventing proper DNA replication (generally bacteriostatic).
What are common side effects associated with many antibiotics?
Gastrointestinal disturbances (e.g., nausea, diarrhea) are common due to effects on gut flora and rapid-turnover cells in the GI tract. Some antibiotics can also cause hypersensitivity reactions or, in rare cases, anaphylaxis.
Why is antibiotic resistance a growing concern, and how does it arise?
Bacteria can acquire genetic changes (e.g., plasmids encoding β-lactamases) that degrade or modify antibiotics, rendering them ineffective. Overuse or misuse of antibiotics accelerates the spread of resistant strains.
What fundamental feature do cancer cells and many infectious agents (like bacteria) share?
They both originate from a single cell that replicates rapidly. This quick proliferation makes timely intervention crucial, whether tackling tumor growth or a bacterial infection.
Which three key molecular processes form the “central dogma” of biology, and which enzymes carry them out?
- Transcription (DNA → mRNA) via RNA polymerase
- Translation (mRNA → protein) via ribosomes (large and small subunits) plus tRNAs and initiation factors
- Replication (DNA → DNA) via DNA polymerase, helicase, primase, ligase, etc.
In eukaryotic cells, during which phase of the cell cycle does DNA replication occur, and when do transcription and translation happen?
- DNA replication occurs in the S phase (Synthesis phase).
- Transcription and translation happen throughout interphase (G1, S, G2) and can also occur to a lesser extent during M phase, as cells still need to produce proteins.
Why is cancer often described as a collection of diseases rather than a single disease?
“Cancer” is an umbrella term covering many distinct diseases. Each cancer type can involve different cells, genetic mutations, and pathways, making “one cure for all cancers” very challenging.
How can DNA damage lead to cancer, and what are proto-oncogenes vs. tumor suppressor genes?
- DNA damage or mutations (spontaneous or caused by chemicals, viruses, radiation) can alter crucial genes.
- Proto-oncogenes normally promote growth; when mutated (oncogenes), they push cells to proliferate uncontrollably.
- Tumor suppressor genes normally act like brakes; if lost or mutated, cells lose critical “stop” signals.
What is the difference between encapsulated and invasive (metastatic) tumors?
- Encapsulated tumors are localized in one spot with a distinct boundary and are often easier to remove surgically.
- Invasive/metastatic tumors breach their capsule, spread into surrounding tissues, or move to distant sites, making treatment more difficult.
In targeting cancer, why focus on stages like S phase or M phase?
- S phase: Inhibiting DNA synthesis (e.g., blocking polymerases or nucleotide formation) can stop cell replication.
- M phase: Disrupting mitosis (e.g., spindle formation) prevents the final division into new cancer cells.
Many chemotherapeutic agents are most effective against rapidly dividing (cycling) cells.
What is apoptosis, and why is it crucial in both normal physiology and cancer treatment?
Apoptosis is programmed cell death that safely dismantles and removes damaged or unneeded cells. In cancer therapy, many drugs aim to push cancer cells with DNA damage into apoptosis so they self-destruct rather than continue to proliferate.
How do the extrinsic and intrinsic apoptosis pathways differ?
- Extrinsic: Triggered by external death signals (e.g., FasL binding Fas receptor), leading to activation of caspases 8/10 → caspases 3, 6, 7 → DNA breakdown.
- Intrinsic: Triggered internally (often by DNA damage) via p53, which increases pro-apoptotic proteins (e.g., Bax, Bad). This disrupts mitochondrial membranes (releasing cytochrome c), activating caspases 9 → caspases 3, 6, 7 → DNA breakdown.
Which main goals are highlighted for learning about cancer pharmacology?
- Outline the principles of cancer development.
- Relate cell signaling in cancer and cell death to specific drug mechanisms.
- Describe treatment strategies linked to cancer’s development principles.
- Explain how treatments can target unique cancer cell features vs. normal cells.
Why does this module also focus on anti-infective (antibiotic) therapies alongside cancer therapies?
Both aim to target rapidly replicating cells (or organisms). Infectious microbes (bacteria/viruses) also rely on key processes (DNA replication, protein synthesis), offering parallels to cancer cell targeting—though with different specific molecular targets.
What are the broad classes of targets for antibiotics?
- Cell wall synthesis (e.g., β-lactam antibiotics).
- Protein synthesis (ribosomal inhibitors).
- Nucleic acid synthesis (inhibiting DNA replication or transcription).
- Folate metabolism (blocking bacterial folate pathways).
Which bacterial features differ from human (eukaryotic) cells and can be exploited by antibiotics?
- Cell wall (peptidoglycan) absent in eukaryotes.
- Different ribosome structure (70S vs. 80S in eukaryotes).
- Distinct enzymes (e.g., DNA gyrase, dihydropteroate synthase).
- Plasmids for antibiotic resistance can appear, necessitating careful drug choice.
In the context of bacteria, which processes are commonly targeted by antibiotics?
- Cell wall biosynthesis (e.g., β-lactams).
- Protein synthesis (target 30S or 50S ribosomal subunits).
- Nucleic acid synthesis (DNA gyrase, RNA polymerase).
- Folate synthesis (unique steps not found in humans).
How do β-lactam antibiotics (like penicillins, cephalosporins) kill bacteria?
They block the transpeptidation step that cross-links peptidoglycan layers in the bacterial cell wall. This “β-lactam ring” structure irreversibly inhibits the enzyme (transpeptidase), causing cell wall destabilization and bacterial lysis (bactericidal effect).
Why are sulfonamides and trimethoprim considered bacteriostatic rather than bactericidal?
They block folate production (essential for DNA/RNA synthesis), but do not directly kill bacteria on the spot. Instead, they halt bacterial growth, giving the host’s immune system a chance to clear the infection.
Name two key enzymes in prokaryotic DNA replication and their roles.
- DNA gyrase (topoisomerase II): Introduces negative supercoils to relieve strain during replication.
- DNA polymerase III: Main enzyme synthesizing new DNA strands, requiring primase and other factors.
What do DNA gyrase inhibitors do, and when are they especially useful?
- Mechanism: They inhibit DNA gyrase, blocking the supercoiling necessary for bacterial DNA replication.
- Usefulness: Often used when bacteria become resistant to β-lactams or other major antibiotic classes. They are usually considered bacteriostatic.
Why are bacterial ribosomes a good target for antibiotics like macrolides or tetracyclines?
Bacterial ribosomes differ in structure (70S) compared to eukaryotic (80S) ribosomes, allowing selective inhibition of bacterial protein synthesis with less effect on human cells.
What are polymyxins, and why are they mostly used as topical agents?
Polymyxins are antibiotics with high systemic toxicity and poor GI absorption, making them unsuitable for oral or IV use. They are therefore mostly applied topically (e.g., for skin infections).
Why is bacitracin also used primarily for superficial infections rather than systemic treatment?
Like polymyxins, bacitracin can be toxic systemically. Using it topically for small superficial wounds or skin infections helps localize its effects and avoid systemic toxicity.
How does vancomycin inhibit bacterial cell wall synthesis?
It binds to the D-alanyl-D-alanine terminus of peptidoglycan precursors, blocking the transpeptidation (cross-linking) step required for bacterial cell wall formation.
Why is vancomycin often reserved for serious or resistant infections (e.g., MRSA)?
Vancomycin is a potent, bactericidal antibiotic, traditionally used as a “last resort” to preserve its effectiveness for highly drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA).
Define antibiotic resistance in simple terms.
Antibiotic resistance occurs when bacteria evolve (through genetic changes) to survive drug treatments that once killed them, making these drugs less or no longer effective.
What human behavior commonly drives the development of antibiotic resistance?
Incomplete or improper use of antibiotics (e.g., stopping treatment early or using them for viral infections) selects for more resilient bacteria, accelerating resistance in the microbial population.
Name two mechanisms bacteria can develop to evade antibiotics.
- Producing enzymes (e.g., β-lactamases) that degrade or modify the antibiotic. 2. Changing drug targets (e.g., altered penicillin-binding proteins) so the antibiotic no longer binds effectively.
Why do topical or narrow-spectrum antibiotics often reduce the risk of resistance compared to broad-spectrum oral antibiotics?
Topical/narrow-spectrum treatments target specific bacteria at the infection site without broadly affecting other microbes, decreasing the selective pressure for resistance in the wider bacterial community.
How do viruses differ fundamentally from bacteria in terms of replication and survival?
Viruses are acellular and cannot replicate on their own. They hijack host cells for replication, whereas bacteria can often grow and divide independently.
Summarize the general life cycle steps of an RNA virus (like influenza) inside a host cell.
- Attachment to cell receptors 2. Endocytosis into an endosome 3. Uncoating of the viral genome 4. Viral genome replication using host or viral enzymes 5. Viral protein synthesis 6. Assembly of new virions 7. Release (budding or cell lysis)
What is the role of the M2 ion channel in influenza infection, and how does amantadine exploit it?
The M2 channel permits acidification inside the viral particle to uncoat its RNA. Amantadine blocks M2, preventing acidification and halting uncoating, thus inhibiting infection progression.
Why do neuraminidase inhibitors like oseltamivir (Tamiflu) help control influenza spread within a host?
Neuraminidase cleaves sialic acid, allowing newly formed virions to detach from the host cell. By inhibiting neuraminidase, oseltamivir prevents viral release, reducing further infection of nearby cells.
What makes RNA viruses like influenza prone to frequent genetic variation (e.g., H1N1, H5N1)?
Their genetic material (RNA) often mutates rapidly, and reassortment of viral segments can occur, causing antigenic drift or shift, leading to new strains that can evade immunity or current treatments.
How do DNA viruses, such as herpes simplex, replicate differently from RNA viruses?
DNA viruses typically rely on DNA-dependent DNA polymerases (sometimes their own) and may enter the host nucleus for replication. RNA viruses replicate via RNA-dependent mechanisms and often remain in the cytoplasm.
What is the mechanism by which acyclovir inhibits herpes viruses?
Acyclovir is a guanosine (nucleoside) analogue that, when phosphorylated, blocks viral DNA polymerase. It becomes incorporated into the viral DNA chain, causing chain termination and preventing further replication.
Why do drugs like acyclovir have fewer effects on human cells compared to the virus?
Viral DNA polymerases have higher affinity for acyclovir triphosphate than human DNA polymerases do. Also, many normal human cells aren’t actively replicating as much, further minimizing harm.
What is meant by describing a virus infection as a “hostage situation”?
Viruses capture the host cell’s resources (enzymes, nucleotides, ribosomes) for their own replication, essentially forcing the cell to produce new viral particles at the host’s expense.
Explain the basic characteristics of HIV as an RNA retrovirus.
HIV contains RNA that it converts into DNA via reverse transcriptase. That DNA can then integrate into the host genome, allowing HIV to persist and be replicated every time the cell divides.
Which immune cells are the primary targets of HIV, and how does the virus typically enter them?
HIV mainly infects CD4+ T helper cells. It binds the CD4 receptor and a co-receptor like CCR5 or CXCR4, then fuses with the cell membrane to release its RNA genome into the cell.
How does a high mutation rate in HIV complicate treatment?
HIV’s reverse transcriptase lacks proofreading, causing frequent mutations. Resistant strains can arise quickly if therapy is inconsistent or poorly matched, requiring combination treatments to suppress diverse mutants.
What is the function of enfuvirtide in HIV therapy?
Enfuvirtide is a fusion inhibitor that prevents the viral capsid from fusing with the host cell membrane, thus blocking HIV from releasing its RNA into the cytoplasm.
Compare nucleoside reverse transcriptase inhibitors (NRTIs) with non-nucleoside reverse transcriptase inhibitors (NNRTIs).
NRTIs (e.g., abacavir) mimic nucleosides, causing chain termination in viral DNA. NNRTIs (e.g., efavirenz) bind the reverse transcriptase enzyme directly at a non-active site, inactivating it without resembling nucleotides.
Why are protease inhibitors like tipranavir essential in HIV treatment?
HIV’s proteins are made in a long, continuous chain that must be cleaved into functional pieces. Protease inhibitors block the HIV protease, preventing proper viral assembly and reducing infectious virions.
Which side effects commonly appear with HIV antiviral therapy?
GI disturbances (nausea, diarrhea), liver damage, musculoskeletal pain, skin rashes, and sometimes blood disorders due to off-target impacts on dividing cells or metabolism pathways.
What is the significance of “HIV remission,” and why is it exceptionally rare?
“HIV remission” occurs when a patient shows no detectable viral load off standard therapy. It’s rare because HIV integrates into host DNA. The few documented cases often involved extreme interventions like bone marrow transplants.
Why do many antimicrobial or antiviral treatments tend to cause GI and other systemic side effects?
The drugs target replication, which can affect fast-dividing cells (like those in the GI tract or bone marrow). They may also be metabolized or excreted in ways that tax the liver or immune system.
How can healthcare providers and patients cooperate to slow antibiotic and antiviral resistance?
Providers: Prescribe drugs responsibly, use narrow-spectrum agents when possible, educate patients on adherence. Patients: Complete full courses, avoid leftover/expired meds, only use antimicrobials for proven bacterial/viral infections.
Why is it crucial to consider drug penetration and delivery methods when treating infections like pseudomonas or eye infections?
Some bacteria or tissues are hard to reach due to limited blood supply or protective barriers. Choosing the correct dosage form (topical, IV, etc.) is key to ensuring the drug reaches effective concentrations at the infection site.
How does the WHO Essential Medicines List help combat drug resistance?
It prioritizes crucial drugs based on their effectiveness and resistance profiles. By promoting appropriate use (Access/Watch/Reserve categories), it helps preserve antibiotics for when they are most needed.
What is a major challenge in developing new antibiotics and antivirals?
High research and development costs, relatively low financial returns (especially for short-course antibiotics), and rapid resistance emergence in microbes make pharmaceutical investment less appealing.
In summary, what are the main strategies for antiviral therapy across different virus types?
- Block entry (fusion or receptor inhibitors) 2. Prevent genome uncoating or replication (e.g., M2 inhibitors, polymerase blockers) 3. Inhibit viral assembly (protease inhibitors) 4. Stop virion release (e.g., neuraminidase inhibitors) 5. Boost host immunity (e.g., interferons)
Why is inhibiting DNA replication an effective strategy in cancer treatment?
Cancer cells often replicate rapidly. By blocking DNA replication, we slow or stop tumor cell proliferation, aiming to trigger cell death through irreparable DNA damage or cell cycle checkpoints.
What role does topoisomerase play in normal DNA replication?
Topoisomerases relieve the twisting tension (“supercoiling”) that arises when the DNA helix is unwound. They make temporary nicks in the DNA backbone and then reseal them, preventing dangerous breaks during replication.
How do alkylating agents interfere with cancer cell DNA?
They form covalent bonds (alkyl groups) on bases (often guanine), causing cross-links in the same strand (intra-strand) or between strands (inter-strand). This prevents DNA strands from separating, blocking replication and triggering cell death.
What are nitrogen mustards (e.g., cyclophosphamide) and how do they work?
Nitrogen mustards are alkylating agents that require activation (often in the liver). Their active forms form covalent links between guanine bases in DNA, causing replication failure and cell death.
Why is cyclophosphamide termed a “prodrug”?
It is inactive until metabolized by liver enzymes (phase I metabolism) into a more reactive compound, which then alkylates DNA and inhibits cell replication.
What are nitrosoureas (e.g., lomustine), and when might they be especially useful?
Nitrosoureas are lipid-soluble alkylating agents that can cross the blood-brain barrier, making them suitable for treating certain brain tumors. However, they can severely affect bone marrow function.
How do platinum-based drugs like cisplatin, carboplatin, and oxaliplatin damage DNA?
These agents have platinum centers that form covalent links between DNA bases (often guanines), causing intra-strand crosslinks. This halts replication and can trigger cell death.
What are common side effects of platinum-based chemotherapeutics like cisplatin?
They frequently cause severe nausea/vomiting and can be toxic to kidneys (nephrotoxicity). Some, like carboplatin, have less renal toxicity but may cause more myelosuppression.
What are antimetabolites, and how do they broadly disrupt DNA synthesis?
Antimetabolites are structural analogues of normal metabolites (e.g., folate, nucleotides). They block key enzymes or get misincorporated into DNA, disrupting nucleotide production or replication.
How does methotrexate block nucleotide synthesis?
Methotrexate is a folate antagonist that competitively inhibits dihydrofolate reductase. This prevents the formation of tetrahydrofolate, which is essential for thymidylate (dTMP) and purine synthesis.
Why does a high dietary folate intake reduce methotrexate’s effectiveness?
Abundant folate competes with methotrexate for dihydrofolate reductase, reducing the drug’s ability to inhibit the enzyme and thereby diminishing its anticancer effect.
What types of side effects are typical of methotrexate therapy?
Like many chemotherapy drugs, it often causes bone marrow suppression (lower blood counts), GI/mucosal damage (ulcers, diarrhea), and nausea due to its impact on rapidly dividing cells.
How does 5-fluorouracil (5-FU) inhibit DNA synthesis?
5-FU forms fraudulent nucleotides that block thymidylate synthase, preventing the conversion of dUMP to dTMP. No thymidylate means no thymine for DNA, leading to halted replication and cell death.
Besides inhibiting thymidylate synthase, how else can 5-FU harm cells?
It can produce abnormal RNA and DNA precursors (e.g., 5-FUTP, 5-FdUTP), which become misincorporated into RNA/DNA, causing damage that triggers cell death pathways.
What are purine analogues (like fludarabine), and what do they do?
Purine analogues mimic normal purine nucleotides. Once phosphorylated, they bind DNA polymerase or other enzymes, halting DNA chain elongation or purine metabolism, leading to cell death.
How does cytarabine (a nucleoside analogue) block DNA replication?
Cytarabine resembles deoxycytidine. After phosphorylation inside the cell, it inhibits DNA polymerase, preventing the addition of new nucleotides and causing chain termination.
What common side effects occur with antimetabolites (e.g., methotrexate, 5-FU, cytarabine)?
They typically produce bone marrow depression, mucosal damage, and nausea/vomiting, because rapidly dividing cells in the blood and GI tract are strongly impacted.
Why are some antibiotics (like doxorubicin) used as anticancer drugs?
Certain antibiotics, initially too toxic for normal infections, can damage cancer cells’ DNA or block topoisomerases. Their toxicity is considered tolerable in the high-stakes context of cancer treatment.
How does doxorubicin (an anthracycline) halt cancer cell growth?
Doxorubicin inhibits topoisomerase II, intercalates between DNA bases, and blocks DNA/RNA polymerases, causing replication/transcription arrest and triggering cell death pathways.
Why is cardiotoxicity a concern with doxorubicin?
Doxorubicin can generate reactive oxygen species and accumulate in cardiac tissue, damaging heart cells and potentially leading to arrhythmias or heart failure, especially with prolonged exposure.
What is bleomycin, and how does it damage tumor cells?
Bleomycin chelates metal ions (often iron) and causes DNA strand breaks, partly through reactive oxygen species generation. It’s especially known to cause lung toxicity in some patients.
How do plant-derived agents generally attack cancer cells?
Many plant-derived drugs disrupt microtubules or inhibit topoisomerases, preventing correct chromosome separation or DNA unwinding. This halts the cell cycle and induces cell death.
What does etoposide do, and from what natural source was it derived?
Etoposide is a semisynthetic derivative from the mandrake root that inhibits topoisomerase II. It prevents resealing of double-stranded breaks, leading to lethal DNA damage in late S/G2 phase cells.
Why can topoisomerase inhibitors lead to more DNA breaks if they stall the enzyme–DNA complex?
When topoisomerase is stuck on the DNA with open nicks, normal replication or mechanical stress can convert single-strand nicks into double-strand breaks, which are often fatal for the cell.
Why are bone marrow cells, hair follicles, and GI epithelium often targeted by chemotherapeutic agents?
They’re rapidly dividing. Agents that block DNA replication tend to hit any fast-proliferating tissues, leading to myelosuppression, alopecia, and GI distress.
What is myelosuppression, and why is it a major concern in chemotherapy?
Myelosuppression is the reduction of blood cell production (red cells, white cells, platelets) in the bone marrow. It can cause anemia, infection risk, and bleeding, requiring careful dose management.
Why is the cell cycle phase an important factor in chemotherapy effectiveness?
Some agents (e.g., antimetabolites) act mainly in S phase, while others (e.g., microtubule inhibitors) target M phase. Timing and drug choice can maximize tumor cell killing when cells are most vulnerable.
Under what circumstance might it be risky to combine certain DNA-damaging antibiotics with radiation therapy?
Both treatments cause DNA damage. Combining them can amplify toxicity and harm normal tissues severely, risking excessive side effects unless carefully managed.
Why do many alkylating and DNA-binding drugs have issues with nausea and vomiting?
They are often highly reactive, triggering the body’s vomiting reflex through direct or indirect stimulation of chemoreceptor trigger zones. This side effect can be managed with antiemetic medications.
In general, why are combination therapies common in cancer treatment?
Different drugs target different points in replication or metabolic pathways. Using multiple agents can prevent resistance, increase cancer cell kill, and sometimes lower required doses, reducing toxicity.
What characteristics would a truly “ideal” antibiotic have?
It would effectively kill or inhibit all harmful bacteria (including resistant strains) in a patient without harming beneficial gut flora or causing toxicity to the patient. It would also have low potential for resistance development, be easily administered, and maintain favorable pharmacokinetics (e.g., good absorption and tissue penetration).
Why do no current antibiotics fully meet the definition of “ideal”?
Most antibiotics have limited spectra, some cause collateral damage to normal flora, and resistance inevitably emerges. They also may have side effects, require multiple doses, or lack coverage against certain Gram-negative or Gram-positive pathogens.
What are the two major bacterial cell envelope types that make broad-spectrum coverage difficult?
- Gram-positive bacteria have a thick peptidoglycan layer but only one membrane. 2. Gram-negative bacteria have a thinner peptidoglycan layer plus two membranes (inner & outer), which often makes them more resistant to antibiotics due to limited permeability and active efflux pumps.
How do antibiotics typically become ineffective against bacteria over time?
Bacteria develop resistance mechanisms like: * Target modifications (e.g., altered PBPs or ribosomes) * Enzymatic degradation (e.g., β-lactamases) * Efflux pumps that expel the drug * Reduced uptake or permeability changes. These reduce or negate the antibiotic’s effect.
Why are β-lactam antibiotics (like penicillins, cephalosporins, carbapenems) important, and how do they face resistance challenges?
β-lactams inhibit cell wall synthesis by binding penicillin-binding proteins. They are broad-spectrum and have saved countless lives. However, resistance emerges from modified PBPs or β-lactamases (enzymes that hydrolyze the β-lactam ring), reducing these drugs’ efficacy.
How do β-lactamase inhibitors (like clavulanic acid, avibactam) help restore effectiveness of certain β-lactam antibiotics?
These inhibitors irreversibly bind many β-lactamases, neutralizing the enzyme that deactivates β-lactam antibiotics, thereby restoring the antibiotics’ activity against bacteria that produce these enzymes.
What physical and chemical properties must an ideal antibiotic have to penetrate Gram-negative bacteria effectively?
Generally, it needs to be small and polar enough to pass through outer membrane porins, yet also balanced in structure to cross the inner membrane. It must avoid active efflux, and remain stable long enough to act on intracellular targets.
What is the debate between broad-spectrum vs. narrow-spectrum (“precision”) antibiotics?
- Broad-spectrum: Covers many pathogens (useful for empirical therapy) but can harm normal flora and promote wider resistance. * Narrow-spectrum: Targets specific bacteria (reducing flora disruption) but requires accurate, rapid diagnostics and may be too specialized in mixed infections or for immediate empirical use.
Why is multi-target binding considered helpful against resistance?
An antibiotic that binds multiple targets (or a single target at multiple sites) makes it harder for bacteria to develop one-step mutations. This lowers the risk of quick resistance and can extend the drug’s useful lifespan.
Why is discovering completely new antibiotic classes so difficult?
There is a lack of new chemical scaffolds that meet the strict requirements (penetration, low toxicity, target specificity). Also, historical antibiotic leads mainly came from natural products, and many of those have been heavily explored. New large-scale screens rarely yield truly novel, clinically viable leads.
Which cellular processes do most antibiotics target in bacteria?
Common antibiotic targets include: * Cell wall synthesis (peptidoglycan) * Ribosomes (bacterial 30S or 50S subunits) * DNA replication (e.g., topoisomerases, gyrase) * Folate or nucleotide synthesis. These processes are vital for bacterial growth and survival.
Which key processes do chemotherapy drugs typically target in cancer cells?
They often target: * DNA replication/structure (e.g., alkylators, topoisomerase inhibitors) * Mitotic spindle (microtubules) * Cell cycle regulators (CDK inhibitors) * Hormone receptors (in hormone-sensitive tumors). Overall, they aim to disrupt rapid cell division or induce apoptosis.
Why might some antibiotics (e.g., certain cytotoxic “antibiotics” like doxorubicin) be used in cancer therapy?
Some antibiotics interfere with DNA function or topoisomerases in eukaryotic cells as well, causing cell death. These antibiotic compounds (initially discovered against bacteria) happen to have broad DNA-binding or ROS-generating activities that can kill tumor cells, though they are often too toxic for standard infectious disease use.
Why don’t typical antibiotics harm eukaryotic cells the same way they harm bacteria?
Many classic antibiotics target bacteria-specific structures (e.g., peptidoglycan) or unique bacterial ribosomes. Eukaryotic cells lack these bacterial-specific features, so those antibiotics have little direct effect on human cells at normal doses.
What is the main difference between the intended outcomes of antibiotic vs. anti-cancer treatments?
- Antibiotics aim to eliminate infecting bacteria without killing host cells. * Anti-cancer drugs often damage or kill rapidly dividing host cells (tumor cells), accepting certain toxicity to normal tissues as part of therapy.
How can one ensure that using an antibiotic doesn’t inadvertently cause the same effects as a cytotoxic anti-cancer drug?
Strategies include: 1. Selecting antibiotics with highly bacteria-specific targets. 2. Using doses that inhibit bacterial processes but aren’t toxic to host cells. 3. Designing or choosing drug delivery that doesn’t accumulate in normal tissues. 4. Confirming that the mechanism (e.g., blocking bacterial ribosome) doesn’t overlap significantly with essential eukaryotic processes.
In what cases might an antibiotic truly be co-opted for cancer therapy, and what would be the trade-off?
Certain “antibiotic” molecules (like doxorubicin or bleomycin) that cause DNA damage can kill cancer cells. The trade-off is potential toxicity to normal human cells, so they’re used in carefully controlled doses in oncology rather than as standard infection treatments.
What are examples of antibiotic-derived anti-cancer agents?
- Doxorubicin (an anthracycline) * Bleomycin * Daunorubicin * Mitomycin C. All originally came from microbial sources, but they are used primarily for chemotherapy due to their potent cytotoxicity.
