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Pharmacology: Antimicrobial Chemotherapy and Drug Interactions
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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

    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)</p> Signup and view all the answers

    Which of the following antibacterial drugs inhibits protein synthesis?

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

    Echinocandins inhibit cell wall synthesis.

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

    Paul Ehrlich used Salvarsan (arsphenamine) to treat cancer.

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

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

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

    Penicillins are lipid soluble and can enter mammalian cells easily.

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

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

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

    Cephalosporins are generally acid labile.

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

    Cephalosporins have a similar mechanism of action to penicillins.

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

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

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

    Tetracyclines are bactericidal against Gram-positive bacteria.

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

    Amphenicols are effective against Gram-negative bacteria.

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

    Tenofovir is a non-nucleoside reverse transcriptase inhibitor.

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

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

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

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

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

    Truvada contains emtricitabine/tenofovir alafenamide.

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

    Penicillins are lipid insoluble and cannot enter mammalian cells easily.

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

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

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

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

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

    Allergic reactions to penicillins are dose-dependent.

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

    Penicillins are lipid soluble and can enter mammalian cells easily.

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

    Tetracyclines are bactericidal against Gram-positive bacteria.

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

    Ergosterol is a distinctive sterol found in human cell membranes.

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

    What is the mechanism of action of polyenes?

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

    Amphotericin B has good oral absorption.

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

    Azoles are broad-spectrum synthetic fungicidal antifungal drugs.

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

    All antifungal drugs are fungicidal.

    <p>False</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</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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    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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