Pharmacology: Antimicrobial Chemotherapy and Drug Interactions

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

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.