Pharmacology: Antimicrobial Chemotherapy and Drug Interactions
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Questions and Answers

What is the main difference between -cidal and -static antimicrobial drugs?

  • Their spectrum of activity
  • Their potency
  • Their mechanism of action (correct)
  • Their pharmacokinetics

    • The minimum inhibitory concentration (MIC) is a measure of the antimicrobial drug's potency.

    False (B)

    What is the term for the relationship between the dose of a drug and its resulting effect?

    Dose/concentration-response relationship

    The volume of distribution of a drug is related to its _______________ in the body.

    <p>distribution</p> Signup and view all the answers

    Match the following terms with their definitions:

    <p>Pharmacodynamics = Study of the effects of drugs on the body Pharmacokinetics = Study of the body's effects on drugs Mechanism of action = How a drug interacts with its target Potency = The maximum effect of a drug</p> Signup and view all the answers

    What is the purpose of the broth microdilution test in antimicrobial susceptibility testing?

    <p>To determine the minimum inhibitory concentration (MIC) (D)</p> Signup and view all the answers

    Which of the following antibacterial drugs inhibits protein synthesis?

    <p>Aminoglycosides (C)</p> Signup and view all the answers

    Echinocandins inhibit cell wall synthesis.

    <p>True (A)</p> Signup and view all the answers

    What is the mechanism of action of reverse transcriptase inhibitors?

    <p>They inhibit DNA synthesis.</p> Signup and view all the answers

    Tetracyclines are a class of antibacterial drugs that ____________________.

    <p>inhibit protein synthesis</p> Signup and view all the answers

    Match the following antibacterial drugs with their mechanisms of action:

    <p>Aminoglycosides = inhibit protein synthesis Penicillins = inhibit cell wall synthesis Echinocandins = inhibit cell wall synthesis Tegavir = inhibit integrase activity</p> Signup and view all the answers

    Which of the following anti-HIV drugs inhibits protease activity?

    <p>Navir (B)</p> Signup and view all the answers

    What is the primary goal of antimicrobial chemotherapy?

    <p>To target pathogens while being innocuous to the host (A)</p> Signup and view all the answers

    Paul Ehrlich used Salvarsan (arsphenamine) to treat cancer.

    <p>False (B)</p> Signup and view all the answers

    What is the name of the scientist who used Salvarsan to treat syphilis?

    <p>Paul Ehrlich</p> Signup and view all the answers

    Antimicrobial chemotherapy includes _______________ drugs.

    <p>antibacterial, antifungal, antiparasitic, and antiviral</p> Signup and view all the answers

    Match the following antibiotic classes with their corresponding type:

    <p>Aminoglycosides = 1. Antibacterials Cephalosporins = 1. Antibacterials Echinocandins = 2. Antifungals Polyenes = 2. Antifungals</p> Signup and view all the answers

    What is the term for the use of drugs that are selectively toxic to pathogens but innocuous to the host?

    <p>Antimicrobial chemotherapy (C)</p> Signup and view all the answers

    What is the minimum inhibitory concentration (MIC) of a drug?

    <p>The lowest concentration of a drug required to inhibit the visible growth of a microorganism (B)</p> Signup and view all the answers

    A -cidal drug is always lethal to the target organism.

    <p>True (A)</p> Signup and view all the answers

    What is the purpose of dose optimisation in antimicrobial therapy?

    <p>To achieve optimal treatment, avoid toxicity, and suppress drug resistance.</p> Signup and view all the answers

    A broad spectrum drug is effective against a wide range of ____________________.

    <p>species</p> Signup and view all the answers

    What is the PK/PD consideration for time-dependent antimicrobial drugs?

    <p>Time &gt; MIC (A)</p> Signup and view all the answers

    Match the following terms with their corresponding descriptions:

    <p>-cidal = lethal to the target organism -static = slow down microbial growth by blocking replication MIC = minimum inhibitory concentration AUC = area under the concentration-time curve</p> Signup and view all the answers

    What is an important consideration for antimicrobial drug therapy in patients with comorbidities such as HIV?

    <p>Drug-drug interactions</p> Signup and view all the answers

    What is an example of a synthetic penicillin with broad spectrum and no beta-lactamase resistance?

    <p>Amoxicillin (B)</p> Signup and view all the answers

    Penicillins are lipid soluble and can enter mammalian cells easily.

    <p>False (B)</p> Signup and view all the answers

    What is the purpose of clavulanic acid?

    <p>A beta-lactamase inhibitor</p> Signup and view all the answers

    The 5th generation of cephalosporins has an expanded spectrum against _______________ bacteria.

    <p>Gram-positive, including MRSA</p> Signup and view all the answers

    Match the following penicillin resistance mechanisms with their descriptions:

    <p>Alterations in PBPs = Decrease drug binding and antibacterial activity Production of B-lactamase = Inactivate B-lactams Prevention of B-lactams from accessing pore channels = Reach PBPs in cell membrane of G- bacteria</p> Signup and view all the answers

    What is a common adverse effect of prolonged use of penicillins?

    <p>Superinfection (A)</p> Signup and view all the answers

    Which of the following antibacterial drugs inhibits protein synthesis by inhibiting tRNA binding?

    <p>Tetracyclines (A)</p> Signup and view all the answers

    Cephalosporins are generally acid labile.

    <p>False (B)</p> Signup and view all the answers

    Cephalosporins have a similar mechanism of action to penicillins.

    <p>True (A)</p> Signup and view all the answers

    What is the primary route of excretion for most cephalosporins?

    <p>Renal tubular secretion</p> Signup and view all the answers

    What is the mechanism of action of aminoglycosides?

    <p>Aminoglycosides inhibit protein synthesis by binding to the 30S ribosomal subunit, causing misreading of mRNA.</p> Signup and view all the answers

    Macrolides inhibit protein synthesis by preventing the transfer of tRNA with the growing peptide chain from the ______ site to the P site.

    <p>A</p> Signup and view all the answers

    Match the following antibacterial drugs with their mechanisms of action:

    <p>Amphenicols = b) Inhibit peptide bond formation Aminoglycosides = a) Inhibit codon-anticodon interaction Tetracyclines = c) Inhibit aa-tRNA binding to A site Macrolides = d) Prevent transfer of tRNA with growing peptide chain from A site to P site</p> Signup and view all the answers

    Which of the following antibacterial drugs inhibits protein synthesis by inhibiting transpeptidation?

    <p>Amphenicols (D)</p> Signup and view all the answers

    Cross-reactivity between penicillins and cephalosporins causes adverse drug reactions (ADRs) in some patients.

    <p>True (A)</p> Signup and view all the answers

    What is the common feature of antibacterial drugs that inhibit protein synthesis?

    <p>They all inhibit one of the four key steps in bacterial protein synthesis: initiation, tRNA binding, translocation, or elongation.</p> Signup and view all the answers

    What is the mechanism of action of Aminoglycosides?

    <p>Inhibiting protein synthesis (D)</p> Signup and view all the answers

    Tetracyclines are bactericidal against Gram-positive bacteria.

    <p>False (B)</p> Signup and view all the answers

    What is the common side effect of Aminoglycosides?

    <p>Ototoxicity and Nephrotoxicity</p> Signup and view all the answers

    Chloramphenicol is primarily eliminated through the ______________ pathway.

    <p>hepatic</p> Signup and view all the answers

    What is a common side effect of Tetracyclines?

    <p>GI disturbance (B)</p> Signup and view all the answers

    Amphenicols are effective against Gram-negative bacteria.

    <p>True (A)</p> Signup and view all the answers

    Match the following antibacterial drugs with their corresponding side effects:

    <p>Aminoglycosides = Ototoxicity and Nephrotoxicity Tetracyclines = GI disturbance and bone marrow suppression Amphenicols = Grey baby syndrome and bone marrow suppression</p> Signup and view all the answers

    Why are Tetracyclines contraindicated in children and pregnant women?

    <p>They can cause staining and deformities in teeth and bones.</p> Signup and view all the answers

    Aminoglycosides are administered through ______________ routes.

    <p>intramuscular or intravenous</p> Signup and view all the answers

    What is the effect of HIV protease inhibitors on the Gag-Pol fusion polyprotein?

    <p>It prevents the cleavage of the polyprotein into individual proteins (A)</p> Signup and view all the answers

    Tenofovir is a non-nucleoside reverse transcriptase inhibitor.

    <p>False (B)</p> Signup and view all the answers

    What is the mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTIs)?

    <p>NNRTIs bind to a distinct binding site - a hydrophobic pocket in the p66 subunit, causing a conformational change that inhibits enzyme activity.</p> Signup and view all the answers

    HIV protease inhibitors are often combined with a low dose of _______________, a potent CYP3A4 inhibitor, to enhance their efficacy.

    <p>ritonavir</p> Signup and view all the answers

    Match the following anti-HIV drug classes with their corresponding mechanisms of action:

    <p>HIV reverse transcriptase inhibitors = Inhibit the activity of HIV reverse transcriptase HIV protease inhibitors = Inhibit the cleavage of the Gag-Pol fusion polyprotein Non-nucleoside reverse transcriptase inhibitors (NNRTIs) = Bind to a distinct binding site in the p66 subunit, causing a conformational change</p> Signup and view all the answers

    What is the primary mechanism of action of reverse transcriptase inhibitors in anti-HIV treatment?

    <p>Inhibition of reverse transcription (B)</p> Signup and view all the answers

    True or False: Tenofovir alafenamide has similar toxicity to tenofovir disoproxil.

    <p>False (B)</p> Signup and view all the answers

    What is the purpose of pharmacokinetic enhancers in anti-HIV treatment?

    <p>To increase the bioavailability and plasma concentrations of anti-HIV drugs.</p> Signup and view all the answers

    The volume of distribution of a drug is related to its _______________ in the body.

    <p>distribution</p> Signup and view all the answers

    Match the following anti-HIV drug classes with their mechanisms of action:

    <p>Nucleoside reverse transcriptase inhibitors (NRTIs) = Inhibition of reverse transcription Non-nucleoside reverse transcriptase inhibitors (NNRTIs) = Inhibition of reverse transcription Protease inhibitors (PIs) = Inhibition of protease activity</p> Signup and view all the answers

    HIV transmission can occur through ______________, including sexual contact, blood transfusion, and mother-to-child transmission.

    <p>various modes</p> Signup and view all the answers

    True or False: PrEP (Pre-Exposure Prophylaxis) and PEP (Post-Exposure Prophylaxis) are identical HIV prevention strategies.

    <p>False (B)</p> Signup and view all the answers

    What is the primary function of HIV integrase?

    <p>To integrate the proviral DNA into the host cell genome (A)</p> Signup and view all the answers

    The use of antiretroviral therapy (ART) can lead to multidrug resistance in HIV patients.

    <p>True (A)</p> Signup and view all the answers

    What is the term for the relationship between the viral load and the transmission of HIV?

    <p>U=U (Undetectable = Untransmittable)</p> Signup and view all the answers

    The HIV treatment regimen that includes a combination of NRTIs and INSTIs is known as _______________________.

    <p>HAART (Highly Active Antiretroviral Therapy)</p> Signup and view all the answers

    Match the following anti-HIV drugs with their mechanisms of action:

    <p>Elvitegravir = HIV integrase strand transfer inhibitor Rilpivirine = Non-nucleoside reverse transcriptase inhibitor (NNRTI)</p> Signup and view all the answers

    The use of condoms is highly effective in preventing HIV transmission and certain sexually transmitted infections (STIs).

    <p>True (A)</p> Signup and view all the answers

    What is the mechanism of action of nucleoside reverse transcriptase inhibitors (NRTIs)?

    <p>Terminate elongation of viral DNA (B)</p> Signup and view all the answers

    Truvada contains emtricitabine/tenofovir alafenamide.

    <p>False (B)</p> Signup and view all the answers

    What is the primary goal of using nucleoside reverse transcriptase inhibitors (NRTIs) in HIV treatment?

    <p>To terminate the elongation of viral DNA by incorporating analogues of nucleosides into the viral genome.</p> Signup and view all the answers

    Tenofovir disoproxil fumarate is converted to ________ at different locations in the body.

    <p>tenofovir</p> Signup and view all the answers

    Match the following anti-HIV drugs with their formulations:

    <p>Truvada = Descovy Emtricitabine/tenofovir alafenamide = Emtricitabine/tenofovir disoproxil fumarate</p> Signup and view all the answers

    Tenofovir alafenamide is a prodrug of tenofovir that increases oral absorption.

    <p>True (A)</p> Signup and view all the answers

    What is the essential component of the β-lactam ring for antibacterial activity?

    <p>The β-lactam ring itself (B)</p> Signup and view all the answers

    Penicillins are lipid insoluble and cannot enter mammalian cells easily.

    <p>True (A)</p> Signup and view all the answers

    What is the primary component of the 3-dimensional lattice in bacterial cell walls?

    <p>Peptidoglycan</p> Signup and view all the answers

    The peptidoglycan structure in bacterial cell walls consists of linear strands of two alternating aminosugars, namely ____________________ and N-acetyl-glucosamine (NAG).

    <p>N-acetyl-muramic acid (NAMA)</p> Signup and view all the answers

    Match the following β-lactam drugs with their characteristics:

    <p>Penicillins = Natural or semisynthetic Cephalosporins = Semisynthetic or totally synthetic</p> Signup and view all the answers

    β-lactamase resistance is a common mechanism of resistance to β-lactam drugs.

    <p>True (A)</p> Signup and view all the answers

    What is the purpose of penicillin binding proteins (PBPs) in bacteria?

    <p>To facilitate cell wall synthesis</p> Signup and view all the answers

    Which of the following is a common adverse effect of prolonged use of penicillins?

    <p>Hypersensitivity reactions (C)</p> Signup and view all the answers

    What is the primary mechanism of β-lactamase resistance in bacteria?

    <p>Producing β-lactamase enzymes (A)</p> Signup and view all the answers

    Penicillins are generally well-tolerated and have minimal adverse effects.

    <p>False (B)</p> Signup and view all the answers

    What is the role of penicillin binding proteins (PBPs) in bacterial cell walls?

    <p>Penicillin binding proteins (PBPs) are enzymes involved in the final step of peptidoglycan synthesis, and penicillins inhibit their activity, causing cell wall lysis and ultimately, bacterial death.</p> Signup and view all the answers

    The peptidoglycan layer in bacterial cell walls is composed of a backbone of _______________ and _______________.

    <p>N-acetylglucosamine and N-acetylmuramic acid</p> Signup and view all the answers

    Match the following penicillins with their characteristics:

    <p>Natural penicillins = Narrow spectrum, susceptible to β-lactamase Semisynthetic penicillins = Broad spectrum, resistant to β-lactamase Synthetic penicillins = Narrow spectrum, not susceptible to β-lactamase</p> Signup and view all the answers

    What is the primary route of excretion for most penicillins?

    <p>Renal excretion (C)</p> Signup and view all the answers

    Allergic reactions to penicillins are dose-dependent.

    <p>False (B)</p> Signup and view all the answers

    What is the purpose of clavulanic acid in Augmentin?

    <p>Clavulanic acid is a β-lactamase inhibitor that prevents the breakdown of amoxicillin by β-lactamase enzymes, allowing the antibiotic to be effective against β-lactamase-producing bacteria.</p> Signup and view all the answers

    What is the primary mechanism of resistance to penicillins in gram-negative bacteria?

    <p>Production of β-lactamase (C)</p> Signup and view all the answers

    Penicillins are lipid soluble and can enter mammalian cells easily.

    <p>False (B)</p> Signup and view all the answers

    What is the function of clavulanic acid in Augmentin?

    <p>Clavulanic acid is a β-lactamase inhibitor that prevents the breakdown of amoxicillin by β-lactamase-producing bacteria.</p> Signup and view all the answers

    The 5th generation of cephalosporins has an expanded spectrum against _________________ bacteria.

    <p>MRSA (methicillin-resistant Staphylococcus aureus)</p> Signup and view all the answers

    Match the following penicillin resistance mechanisms with their descriptions:

    <p>Prevent β-lactams from accessing and traversing pore channels and reaching PBPs in the cell membrane of gram-negative bacteria = A Produce alterations in PBPs → decreased drug binding and subsequent ↓ antibacterial activity = B Produce β-lactamase to inactivate β-lactams = C</p> Signup and view all the answers

    What is the common feature of antibacterial drugs that inhibit protein synthesis?

    <p>They all act on the 70S bacterial ribosome (A)</p> Signup and view all the answers

    Tetracyclines are bactericidal against Gram-positive bacteria.

    <p>False (B)</p> Signup and view all the answers

    What is the primary route of excretion for most penicillins?

    <p>The renal route (90% by tubular secretion)</p> Signup and view all the answers

    Penicillins are eliminated via the ____________________ route.

    <p>renal</p> Signup and view all the answers

    What is the primary site of infection for systemic fungal infections?

    <p>All of the above (D)</p> Signup and view all the answers

    Ergosterol is a distinctive sterol found in human cell membranes.

    <p>False (B)</p> Signup and view all the answers

    What is a challenge in developing antifungal drugs?

    <p>Biological similarities between humans and fungi as eukaryotes</p> Signup and view all the answers

    Echinocandins, a class of antifungal drugs, inhibit the synthesis of ___________ in fungal cell walls.

    <p>β-1,3-glucan</p> Signup and view all the answers

    Match the following antifungal drug classes with their mechanisms of action:

    <p>Polyenes = Alter cell membrane integrity or permeability Allylamines = Alter cell membrane integrity or permeability Azoles = Alter cell membrane integrity or permeability Echinocandins = Inhibit cell wall synthesis</p> Signup and view all the answers

    Antifungal drugs can be toxic to humans and require strict monitoring.

    <p>True (A)</p> Signup and view all the answers

    What is the mechanism of action of polyenes?

    <p>Formation of pores in fungal cell membranes (C)</p> Signup and view all the answers

    Amphotericin B has good oral absorption.

    <p>False (B)</p> Signup and view all the answers

    What is the primary goal of antifungal therapy for invasive candidiasis?

    <p>To achieve fungicidal activity</p> Signup and view all the answers

    Amphotericin B is primarily eliminated through the ____________________ pathway.

    <p>faecal</p> Signup and view all the answers

    Match the following antifungal drugs with their primary uses:

    <p>Amphotericin B = Systemic infections, including invasive candidiasis Liposomal formulations = Reducing toxicity of amphotericin B</p> Signup and view all the answers

    Nephrotoxicity is a common side effect of amphotericin B.

    <p>True (A)</p> Signup and view all the answers

    What is the benefit of using liposomal formulations of amphotericin B?

    <p>Reduced toxicity</p> Signup and view all the answers

    What type of fungal infection is treated with terbinafine?

    <p>Fungal infection of the nail bed, matrix, or plate (C)</p> Signup and view all the answers

    Azoles are broad-spectrum synthetic fungicidal antifungal drugs.

    <p>False (B)</p> Signup and view all the answers

    What is the name of the enzyme that is inhibited by allylamines in the ergosterol biosynthesis pathway?

    <p>Squalene monooxygenase</p> Signup and view all the answers

    The fungal infection caused by dermatophytes that require keratin for growth is _______________________.

    <p>Onychomycosis</p> Signup and view all the answers

    Match the following antifungal drugs with their mechanisms of action:

    <p>Allylamines = Inhibition of squalene monooxygenase Azoles = Inhibition of 14α-demethylase</p> Signup and view all the answers

    What is a factor that contributes to the increased prevalence of fungal infections?

    <p>Increased use of immunosuppressive therapy (A), Better diagnosis and reporting (C), Widespread use of antibiotics (D)</p> Signup and view all the answers

    All antifungal drugs are fungicidal.

    <p>False (B)</p> Signup and view all the answers

    What is the primary goal of antifungal therapy?

    <p>To eradicate the fungal infection</p> Signup and view all the answers

    Antifungal drugs can be classified into four major classes, including _______________ and triazoles.

    <p>polyenes</p> Signup and view all the answers

    Match the following antifungal drug classes with their mechanisms of action:

    <p>Polyenes = Bind to ergosterol in fungal cell membranes Azoles = Inhibit lanosterol 14-α-demethylase Echinocandins = Inhibit cell wall synthesis Flucytosine = Inhibit DNA synthesis</p> Signup and view all the answers

    What is a common side effect of antifungal therapy?

    <p>All of the above (D)</p> Signup and view all the answers

    Study Notes

    Defining Drug Interaction and Unpacking the Core Concepts of Pharmacology

    • Defining drug interaction and unpacking the core concepts of pharmacology is a global initiative
    • Patient outcomes are crucial in pharmacology
    • Chemotherapy is the use of drugs that are selectively toxic to pathogens but innocuous to the host
    • Paul Ehrlich used Salvarsan (arsphenamine) to treat syphilis

    Antimicrobial Chemotherapy

    • Antimicrobial chemotherapy involves the use of antibacterial, antifungal, antiparasitic, and antiviral drugs
    • Target-host specificity is essential in antimicrobial chemotherapy
    • Paul Ehrlich is a pioneer in antimicrobial chemotherapy

    Discovery and Development of Antibiotics

    • 2 main classes of antibacterials: aminoglycosides and tetracyclines
    • 3 main classes of antifungals: macrolides, azoles, and echinocandins
    • Penicillins, cephalosporins, and amphenicols are examples of antibacterials
    • Polyenes and allylamines are examples of antifungals

    Learning Outcomes

    • List the mechanisms of action of antibacterial, antifungal, and anti-HIV drugs
    • Explain the difference in action between -cidal and -static antimicrobial drugs
    • Explain the difference in action between broad-spectrum and narrow-spectrum antimicrobial drugs
    • Explain the principle of broth microdilution to determine the minimum inhibitory concentration and the minimum bactericidal/fungicidal concentration of antimicrobial drugs

    Core Concepts of Pharmacology

    • Pharmacodynamics involves drug-target interaction and mechanism of drug action
    • Pharmacokinetics involves drug absorption, distribution, metabolism, elimination, and bioavailability
    • Drug-target interaction involves affinity, potency, and efficacy

    Antibiotics and Leading Causes of Deaths

    • Antibiotics are crucial in treating and preventing infections

    Mechanisms of Action of Antibacterial Drugs

    • Inhibit cell wall synthesis: penicillins, cephalosporins
    • Inhibit protein synthesis: aminoglycosides, tetracyclines, amphenicols, macrolides
    • Inhibit DNA replication
    • Inhibit metabolism

    Mechanisms of Action of Antifungal Drugs

    • Inhibit cell wall synthesis: echinocandins
    • Alter cell membrane integrity or permeability: polyenes, allylamines, azoles
    • Inhibit mitosis
    • Inhibit DNA synthesis

    Mechanisms of Action of Anti-HIV Drugs

    • Entry inhibitors
    • Reverse transcriptase inhibitors
    • Integrase inhibitors: -tegravir
    • Protease inhibitors: -navir

    Mode of Action of Anti-Bacterial/Fungal Drugs

    • -Cidal: lethal to organism and kills microbes
    • -Static: slow down microbial growth by blocking replication

    Spectrum of Action of Anti-Bacterial/Fungal Drugs

    • Broad-spectrum: effective against a wide range of species
    • Narrow-spectrum: effective against specific species

    Minimum Inhibitory Concentration

    • The lowest concentration of a drug required to inhibit the visible growth of a microorganism
    • Minimum bactericidal/fungicidal concentration: the lowest concentration of a drug required to kill a microorganism

    Antimicrobial Drugs - PK/PD Considerations

    • Time- and concentration-dependent: AUC:MIC
    • Concentration-dependent: Cmax:MIC
    • Time-dependent: Time > MIC
    • Comorbidities: e.g., HIV, obesity
    • Dose optimisation: optimal treatment, avoid toxicity, suppress drug resistance

    Cephalosporins

    • Cephalosporins are similar to penicillins and have cross reactivity, leading to adverse drug reactions (ADRs)
    • The open β-lactam ring in cephalosporins is unrelated to ADRs
    • Similarity in sidechains between 1st and 2nd generation cephalosporins and penicillins contributes to cross reactivity

    Bacterial Protein Synthesis

    • Bacterial protein synthesis involves initiation, tRNA binding, peptide bond formation, translocation, and elongation
    • Inhibitors of bacterial protein synthesis can target one of these four key steps
    • Most inhibitors are bacteriostatic, except for aminoglycosides which are bactericidal

    Aminoglycosides

    • Aminoglycosides inhibit initiation by blocking codon-anticodon interaction, leading to mRNA misreading
    • They bind to the 30S subunit

    Tetracyclines

    • Tetracyclines inhibit tRNA binding to the A site
    • They bind to the 30S subunit

    Amphenicols

    • Amphenicols inhibit transpeptidation by blocking peptide bond formation
    • They bind to the 50S subunit

    Antibacterial Macrolides

    • Macrolides inhibit elongation and/or translocation by preventing transfer of tRNA with the growing peptide from A site to P site
    • They bind to the 50S subunit

    β-Lactams

    • β-Lactams include penicillins and cephalosporins
    • Differences in antibacterial specificity can be explained by interactions between β-lactam drugs and various penicillin binding proteins in bacteria

    Penicillins

    • Examples of β-lactam penicillins include amoxicillin and clavulanic acid
    • Penicillins are acid-stable, lipid-insoluble, and do not enter mammalian cells
    • They are eliminated renally and can cross the blood-brain barrier only if meninges are inflamed

    Penicillin Resistance

    • Alterations in penicillin binding proteins decrease drug binding and antibacterial activity
    • Bacteria can produce β-lactamase, which inactivates β-lactams
    • Augmentin (amoxicillin + clavulanic acid) is used to overcome resistance

    Penicillin Adverse Drug Reactions

    • Opening the β-lactam ring leads to formation of benzylpenicilloyl
    • Type 1 and 2 sensitivity reactions can occur, as well as superinfection (e.g., Candidiasis) with prolonged use

    Cephalosporins

    • 5th generation cephalosporins have expanded Gram-positive activity, including MRSA
    • They have high affinity binding with penicillin binding proteins

    Cephalosporin Pharmacokinetics

    • Cephalosporins are acid-stable and mostly administered parenterally
    • They are distributed in extracellular fluid and can cross the blood-brain barrier to treat meningitis
    • They are excreted mainly through renal tubular secretion

    Aminoglycosides

    • Aminoglycosides are bactericidal and have time- and concentration-dependent activity
    • They are administered intramuscularly or intravenously and eliminated through glomerular filtration
    • Ototoxicity and nephrotoxicity are potential adverse effects

    Tetracyclines

    • Tetracyclines are broad-spectrum, bacteriostatic, and effective against Gram-positive and Gram-negative bacteria
    • They can be administered orally or parenterally
    • Gastrointestinal disturbances, calcium chelation, and staining/deformities in teeth and bones are potential adverse effects

    Amphenicols

    • Amphenicols are broad-spectrum, bacteriostatic, and effective against Gram-positive and Gram-negative bacteria
    • Chloramphenicol is rapidly absorbed orally and hepatatically cleared
    • Bone marrow suppression and grey baby syndrome are potential adverse effects

    HIV Reverse Transcriptase Inhibitors

    • Nucleoside reverse transcriptase inhibitors (NRTIs) are analogues of adenosine, cytidine, guanosine, or thymidine that are phosphorylated to form a triphosphate and incorporated into ssDNA to terminate elongation.
    • The first NRTI, zidovudine or azidothymidine, was approved by the FDA in 1987.
    • Combination drugs, such as Truvada (emtricitabine/tenofovir disoproxil fumarate) and Descovy (emtricitabine/tenofovir alafenamide), are used to treat HIV.
    • Common side effects of NRTIs include GI disturbances (nausea, vomiting) and CNS effects (dizziness).

    Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF)

    • TDF and TAF are prodrugs of tenofovir that increase oral absorption.
    • TDF is converted to tenofovir in the GI tract, while TAF is converted in the plasma.
    • TAF has a lower risk of renal toxicity and decreased bone mineral density compared to TDF.

    Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

    • NNRTIs bind to a hydrophobic pocket in the p66 subunit of HIV reverse transcriptase, causing a conformational change that inhibits enzyme activity.
    • Six NNRTIs have been approved by the FDA, with the first approved in 1996.

    HIV Protease Inhibitors

    • HIV protease inhibitors (PIs) bind to the active site of HIV protease, preventing the cleavage of the Gag-Pol fusion polyprotein.
    • Ten PIs have been approved by the FDA, with the first approved in 1995.
    • PIs are often used in combination with other antiretroviral drugs and can cause side effects such as insulin resistance, hyperlipidemia, and cardiovascular disease.

    HIV Integrase Inhibitors

    • HIV integrase inhibitors bind to integrase and prevent DNA strand transfer.
    • Elvitegravir and cabotegravir are two integrase strand transfer inhibitors (INSTIs) that have been approved by the FDA.

    HIV Treatment and Prevention

    • HIV/AIDS is now a manageable chronic disease that requires life-long antiretroviral therapy (ART).
    • ART aims to achieve viral suppression (< 200 copies/ml) and undetectable levels of viral load (< 20 copies/ml), which makes the virus untransmittable (U=U).
    • HIV treatment regimens include INSTI-based, NNRTI-based, and PI-based combinations.
    • Mutations and drug resistance can occur, and different modes of transmission (unprotected sexual contact, blood-borne exposure, perinatal transmission) require specific prevention strategies (condoms, Treatment as Prevention, PrEP, PEP).

    Antibacterial Drugs

    • Antibacterial drugs can be divided into two main categories: cell wall synthesis inhibitors and bacterial protein synthesis inhibitors.

    Cell Wall Synthesis Inhibitors - β-lactams

    • β-lactams, including penicillins and cephalosporins, inhibit cell wall synthesis by interacting with penicillin binding proteins (PBPs).

    • Penicillins:

      • Natural or semisynthetic
      • Spectrum of action: narrow (e.g., penicillin G) to broad (e.g., amoxicillin)
      • β-lactamase resistant: no (e.g., penicillin G) or yes (e.g., dicloxacillin)
      • Pharmacokinetics: acid stability varies, lipid insoluble, eliminated via renal route
      • Resistance mechanisms: alterations in PBPs, prevention of β-lactam access, and β-lactamase production
      • Adverse drug reactions: hypersensitivity, superinfection, and opening of β-lactam ring
      • Augmentin (amoxicillin + clavulanic acid): overcomes penicillin resistance by inhibiting β-lactamase

    • Cephalosporins:

      • Classified into five generations based on spectrum of action
      • Generation 1: narrow spectrum, Gram+
      • Generation 2-5: increasingly broad spectrum, including Gram-
      • Pharmacokinetics: acid stable, administered parenterally or orally, eliminated via renal tubular secretion
      • Adverse drug reactions: similar to penicillins, with cross-reactivity between penicillins and cephalosporins

    Bacterial Protein Synthesis Inhibitors

    • Inhibit one of four key steps in bacterial protein synthesis: initiation, tRNA binding, transpeptidation, or elongation and translocation
    • Bacteriostatic, except for aminoglycosides which are bactericidal

    Aminoglycosides

    • Inhibit codon-anticodon interaction, causing mRNA misreading
    • Spectrum of action: Gram- and some Gram+ bacteria
    • Pharmacokinetics: administered intramuscularly or intravenously, eliminated by glomerular filtration
    • Adverse drug reactions: ototoxicity and nephrotoxicity

    Tetracyclines

    • Inhibit aa-tRNA binding to the A site
    • Broad spectrum of action: Gram- and Gram+ bacteria
    • Pharmacokinetics: administered orally or parenterally, eliminated via renal route
    • Adverse drug reactions: gastrointestinal disturbance, calcium chelation, and staining of teeth and bones

    Amphenicols

    • Inhibit peptide bond formation
    • Broad spectrum of action: Gram- and Gram+ bacteria
    • Pharmacokinetics: chloramphenicol is rapidly absorbed orally, hepatically cleared, and excreted in the urine
    • Adverse drug reactions: bone marrow suppression and grey baby syndrome

    Macrolides

    • Prevent transfer of tRNA with the growing peptide from A site to P site
    • Similar spectrum of action to penicillins, useful as alternatives
    • Pharmacokinetics: administered orally or IV, substrates for and inhibitors of CYP3A4
    • Adverse drug reactions: gastrointestinal disturbance

    Mechanisms of Resistance to Bacterial PSIs

    • Drug class-specific mechanisms of resistance, including drug modification, active efflux, target modification, and drug degradation

    Inhibition of Ergosterol Biosynthesis

    • Squalene is converted to 2,3-oxidosqualene by squalene monooxygenase, which is inhibited by allylamines
    • Lanosterol is converted to 4,4-dimethyl-Δ8,14,24-trienol by 14α-demethylase, which is inhibited by azoles

    Allylamines

    • Synthetic fungicidal antifungal drugs
    • Inhibit squalene monooxygenase, preventing the conversion of squalene to 2,3-oxidosqualene
    • Example: Terbinafine
      • Treats onychomycosis (fungal infection of the nail bed, matrix, or plate)
      • Major cause of infection: dermatophytes (e.g., Trichophyton rubrum)
      • Highly lipophilic and keratinophilic
      • Oral or topical administration with rapid absorption
      • CYP2D6 inhibitor, potential drug-drug interaction
      • Adverse effects: GI disturbance, rash, and muscle pain

    Azoles

    • Broad-spectrum synthetic fungistatic drugs
    • Inhibit lanosterol 14α-demethylase, preventing the conversion of lanosterol to 4,4-dimethyl-Δ8,14,24-trienol
    • Examples: Imidazoles (e.g., ketoconazole) and triazoles (e.g., itraconazole)
      • Itraconazole:
        • Oral administration with variable absorption
        • Extensive hepatic metabolism
        • Adverse effects: GI disturbance, hepatotoxicity, cardiotoxicity, and a CYP3A4 inhibitor

    Fungal Infections and Antifungal Drugs

    • Factors contributing to increased prevalence of fungal infections
    • Classification of mycoses and relevant site of infection

    Core Concepts of Pharmacology

    • Pharmacodynamics: drug-target interaction, mechanism of action, and adverse effects
    • Pharmacokinetics: drug absorption, distribution, metabolism, elimination, and bioavailability
    • Key concepts: structure-activity relationship, drug selectivity, efficacy, potency, and affinity

    Antifungal Drug Classes

    • Challenges: biological similarities between humans and fungi, toxicity to host, and distinctive sterols
    • Timeline of systemic antifungal drugs
    • Factors to consider: route of administration, spectrum of action, site of infection, renal/hepatic clearance, and drug-drug interaction

    Echinocandins

    • Inhibit cell wall synthesis by binding to β-1,3-glucan synthase
    • Examples: Caspofungin (semisynthetic echinocandin B)
      • Poor oral absorption, i.v. administration
      • Concentration-dependent activity (Cmax:MIC)
      • Fungicidal for Candida species, treating invasive candidiasis
      • Fungistatic for Aspergillus species
      • Adverse effects: nausea, vomiting, diarrhea, and infusion-related reactions

    Polyenes

    • Natural products, broad-spectrum antifungal macrolides
    • Interaction with ergosterol in fungal cell membranes, disrupting stability and fluidity
    • Examples: Amphotericin B
      • Broad spectrum, effective against most fungi and yeasts
      • Poor oral absorption, treat infection of the upper GI tract
      • Systemic infection: slow i.v. infusion
      • Minimal hepatic metabolism, mainly faecal elimination
      • Adverse effects: infusion-related reactions, nephrotoxicity, and interactions with cell membranes
      • Liposomal formulations reduce toxicity

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    Related Documents

    Pharmacology Lecture Notes PDF
    Pharm2210 l18 Drug Study PDF
    PHAR2210 Foundations of Pharmacology Lecture 20 Anti-HIV Drugs PDF
    PHAR2210 Foundations of Pharmacology Lecture 18 PDF
    Lecture 19 Antifungal Drugs PDF

    Description

    This quiz covers the core concepts of pharmacology, including antimicrobial chemotherapy and drug interactions. It discusses the selective toxicity of drugs to pathogens and their effects on patient outcomes.

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