4_DRUG TREATMENT OF RESPIRATORY TRACT INFECTIONS.pptx

DRUGS ACTING ON THE RESPIRATORY TRACT 1 ANTI-MICROBIAL AGENTS USED IN THE TREATMENT OF RESPIRATORY TRACT INFECTIONS Dr Sindwa Kanyimba Lecturer, Pharmacology 2 LEARNING OBJECTIVES List the anti-micr...

DRUGS ACTING ON THE RESPIRATORY TRACT 1 ANTI-MICROBIAL AGENTS USED IN THE TREATMENT OF RESPIRATORY TRACT INFECTIONS Dr Sindwa Kanyimba Lecturer, Pharmacology 2 LEARNING OBJECTIVES List the anti-microbial drug options available for common respiratory tract infections Describe the mechanisms of actions, clinical indications, unwanted effects and contra- indications of anti-microbial drugs used in the treatment of common respiratory tract infections 3 PART 1 DRUG TREATMENT OF COMMON RESPIRATORY TRACT INFECTIONS (RTIs) Dr Sindwa Kanyimba Lecturer, Pharmacology 4 PNEUMONIA Dr Sindwa Kanyimba Lecturer, Pharmacology 5 INTRODUCTION Pneumonia is acute inflammation of the lungs caused by infection (bacterial, viral, fungal or parasitic) Treatment depends on the causative pathogen and the setting in which the pneumonia is acquired Based on the setting in which the pneumonia is acquired, it can be classified as: Community-acquired pneumonia Hospital-acquired pneumonia (nosocomial pneumonia) Pneumonia in the immunocompromised host Aspiration pneumonitis and pneumonia Neonatal pneumonia 6 COMMUNITY-ACQUIRED PNEUMONIA (CAP) CAP develops in people with limited or no contact with medical institutions or settings Treatment is usually empirical, and drug selection is based on likely pathogens, age of patient and severity of illness The most commonly identified pathogens in CAP are:  Streptococcus pneumoniae  Haemophilus influenzae  Chlamydia pneumoniae  Mycoplasma pneumoniae  Legionella species 7 COMMUNITY ACQUIRED PNEUMONIA: COMMON BACTERIAL PATHOGENS PATHOGEN TREATMENT Streptococc Macrolides (azithromycin, clarithromycin) us Beta-lactams (ampicillin, amoxicillin, co- pneumoniae amoxiclav, cefuroxime, cefpodoxime, ceftriaxone, cefotaxime) Carbapenems (imipenem, meropenem) Anti-pneumococcal fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin) Haemophilu Macrolides (azithromycin, clarithromycin) s influenzae Beta-lactams (ceftriaxone, cefotaxime and ampicillin/sulbactam) Fluoroquinolones (levofloxacin, moxifloxacin) Co-trimoxazole Mycoplasma Macrolides (azithromycin, clarithromycin, pneumoniae erythromycin) Telithromycin Chlamydia Doxycycline 8 pneumoniae Fluoroquinolones (levofloxacin, moxifloxacin) COMMUNITY ACQUIRED PNEUMONIA: COMMON BACTERIAL PATHOGENS …. CONT’D PATHOG TREATMENT EN Legionell Macrolides (erythromycin, clarithromycin, a species azithromycin) Fluoroquinolones (levofloxacin, moxifloxacin) Doxycycline Moraxella Beta-lactams (co-amoxiclav, cefuroxime) catarrhali Macrolides (azithromycin, clarithromycin) s Fluoroquinolones (levofloxacin, moxifloxacin) 9 HOSPITAL-ACQUIRED PNEUMONIA (HAP) HAP develops at least 48 hours after hospitalisation The most common pathogens are gram-negative bacilli and staphylococcus aureus Initial treatment is with empirical combination broad-spectrum anti-bacterial drugs based on local sensitivity patterns. This is replaced with definitive treatment with the most specific drug available for the pathogens identified by culture. 10 HOSPITAL-ACQUIRED PNEUMONIA (HAP): COMMON BACTERIAL PATHOGENS PATHOGEN TREATMENT Staphylococ Anti-bacterial drugs with activity against MRSA: cus aureus Vancomycin Linezolid Daptomycin Tigecycline Ceftaroline Co-trimoxazole Gram Beta-lactams (ceftriaxone, cefotaxime) negative Carbapenems (imipenem, meropenem) bacilli Aminoglycosides (gentamicin, tobramycin, amikacin) Fluoroquinolones (ciprofloxacin, levofloxacin) Pseudomona Anti-pseudomonal beta-lactams (tircacillin, piperacillin, s aeruginosa ceftazidime, cefepime) Carbapenems (imipenem, meropenem) Aminoglycosides (gentamicin, tobramycin, amikacin) Fluoroquinolones (ciprofloxacin, levofloxacin) 11 PNEUMONIA IN THE IMMUNOCOMPROMISED HOST Pneumonia in the immunocompromised host is often caused by unusual pathogens Treatment depends on the host defect and pathogen There are many potential pathogens in immunocompromised patients. They include:  Bacteria: gram negative bacteria, S. aureus, S. pneumoniae, H. influenzae, mycobacteria, Norcardia sp, N. meningitidis  Fungi: Aspergillus sp., Candida sp., Mucor, Cryptococcus spp, Pneumocystis jiroveci  Protozoa: Toxoplasma sp.  Viruses: herpes simplex, cytomegalovirus 12 PNEUMONIA IN THE IMMUNOCOMPROMISED HOST PATHOGEN TREATMENT Aspergilllus sp. Voriconazole (drug of choice) Amphotericin B Caspofungin Candida sp. Fluconazole (drug of choice) Voriconazole Amphotericin B Caspofungin Cryptococcus spp Amphotericin B + flucytosine (induction therapy) followed by fluconazole (consolidation therapy) Pneumocystis Co-trimoxazole (drug of choice) jiroveci Pentamidine Atovaquone Caspofungin 13 PNEUMONIA IN THE IMMUNOCOMPROMISED HOST …. CONT’D PATHOGEN TREATMENT Norcardia sp. Co-trimoxazole (drug of choice) Beta-lactams (ceftriaxone, cefotaxime) Macrolides (azithromycin, clarithromycin) Aminoglycosides (amikacin) Carbapenems (imipenem, meropenem) Toxoplasma sp Pyrimethamine + sulfadiazine (first-line treatment) Co-trimoxazole Neisseria Beta-lactams (ceftriaxone, cefotaxime, penicillin meningitidis G) Chloramphenicol Fluoroquinolones (ciprofloxacin) 14 PNEUMONIA IN THE IMMUNOCOMPROMISED HOST …. CONT’D PATHOGEN TREATMENT Herpes Acyclovir, Valacyclovir and Foscarnet simplex Cytomegalovir Ganciclovir, Valganciclovir and Foscarnet us Atypical Combination therapy with the following: mycobacteria Macrolides (clarithromycin, azithromycin) Rifamycins (rifampicin, rifabutin) Fluoroquinolones (moxifloxacin, levofloxacin) Aminoglycosides (amikacin, streptomycin) Others: ethambutol, ethionamide, clofazimine, bedaquiline, linezolid, 15 tetracyclines (doxycycline & ASPIRATION PNEUMONIA Aspiration pneumonia and pneumonitis are caused by inhaling toxic and/or irritant substances, usually gastric contents into the lungs Aspiration can cause chemical pneumonitis (due to direct toxicity or stimulation of an inflammatory response), bacterial pneumonia or lung abscess Aspiration bacterial pneumonia is typically caused by a combination of bacteria including: anaerobic bacteria, gram negative bacteria and gram positive bacteria 16 ASPIRATION PNEUMONIA Anti-bacterial drugs used to treat aspiration pneumonia: Clindamycin Beta-lactams (penicillin G, amoxicillin, amoxicillin/clavulanate) plus metronidazole Carbapenems (imipenem-cilastatin, meropenem) 17 NEONATAL PNEUMONIA Neonatal pneumonia is lung infection in a neonate Pathogens are acquired from the maternal genital tract or the nursery, and include: gram positive cocci (group A and B streptococci, and staphylococcus aureus) and gram negative bacilli (Escherichia coli, Klebsiella sp, and Proteus sp) Treatment is initial broad spectrum anti-bacterial drugs. Changed to organism-specific drugs as soon as possible Initial treatment of choice is vancomycin plus cefotaxime 18 PNEUMONIA: VIRAL CAUSES PATHOGEN TREATMENT Cytomegalovirus (CMV) Ganciclovir, Valganciclovir and Foscarnet Respiratory syncytial virus Ribavirin, Palivizumab and (RSV) Remdesivir Influenza Oseltamivir and Zanamivir, Amantadine and Rimantadine Ribavirin Parainfluenza Ribavirin Varicella Aciclovir Herpes simplex Acyclovir, Valacyclovir and Foscarnet Severe acute respiratory Nirmatrelvir/ritonavir syndrome coronavirus 2 (Paxlovid) and Remdesivir (SARS-COV-2, Covid-19) 19 OTHER RESPIRATORY TRACT INFECTIONS Dr Sindwa Kanyimba Lecturer, Pharmacology 20 LUNG ABSCESS Lung abscess is a necrotizing infection characterised by localised pus It is caused by aspiration of oral secretions by patients who have impaired consciousness, patients with gingivitis or poor oral hygiene, elderly patients and those unable to handle their oral secretions Lung abscess can also occur as a complication of necrotizing pneumonia The most common pathogens are anaerobic bacteria but half of all cases involve both anaerobic and aerobic bacteria The most common aerobic bacteria are streptococci 21 LUNG ABSCESS: TREATMENT Drug of choice is clindamycin (has excellent anaerobic and streptococci coverage) Alternatives: Beta-lactam/beta-lactamase combinations (e.g. amoxicillin-clavulanate, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam) Metronidazole plus penicillin G 22 ACUTE BRONCHITIS Acute bronchitis is inflammation of the upper airways The cause is usually a viral infection (mostly rhinovirus, parainfluenza, influenza A or B, RSV and coronavirus) though it is sometimes a bacterial infection (mostly Mycoplasma pneumoniae, Bordetella pertussis and Chlamydia pneumoniae) Most patients require only symptomatic treatment Patients with underlying lung disease such as COPD are treated with anti-bacterial drugs (amoxicillin, doxycycline and co-trimoxazole) 23 END PART 2 ANTI-MICROBIAL AGENTS USED IN THE TREATMENT OF RESPIRATORY TACT INFECTIONS (RTIs) Dr Sindwa Kanyimba Lecturer, Pharmacology 25 ANTI-BACTERIAL DRUGS Dr Sindwa Kanyimba Lecturer, Pharmacology 26 BETA-LACTAM ANTIBIOTICS Include Penicillins Cephalosporins Carbapenems Mechanism of action Inhibit bacterial transpeptidases, enzymes that cross-link peptidoglycan polymers that are essential for bacterial cell wall integrity. The result is rupture of the bacterial cell wall and subsequent death of the bacterium. Bacterial resistance to beta-lactams Some bacteria produce the enzyme beta-lactamase which degrades beta-lactams 27 BETA-LACTAMASE INHIBITORS Include clavulanic acid, sulbactam, tazobactam They contain a beta lactam ring, but do not have significant antibacterial activity They bind to and inactivate beta-lactamases By inactivating beta-lactamase these compounds enhance the anti-bacterial activity when used in combination with beta- lactams Examples of penicillin + beta-lactamase inhibitor combinations Amoxicillin + clavulanic acid (co-amoxiclav) Ticarcillin + clavulanic acid Piperacillin + tazobactam Ampicillin + sulbactam 28 PENICILLINS Penicillin G RTIs caused by most gram positive cocci and anaerobic bacteria (except bacteroides fragilis) Aminopenicillins (ampicillin and amoxicillin) RTIs caused by Moraxella catarrhalis (co-amoxiclav), haemophilus influenzae, pneumococcus and streptococci Resistance is a problem because of their inactivation by plasmid-mediated penicillinase (H. influenzae are frequently resistant) Formulation with a beta-lactamase inhibitor (e.g. clavulanic acid, sulbactam) can protect them from the enzymatic inactivation 29 PENICILLINS Piperacillin RTIs caused by P. aeruginosa and many other gram- negative bacteria It is susceptible to breakdown by beta-lactamase; thus formulated with tazobactam a beta-lactamase inhibitor Tircacillin RTIs caused by P. aeruginosa 30 CEPHALOSPORINS RTIs caused by many bacteria: Most gram negative bacilli: ceftriaxone, cefotaxime Pneumococcus: cefuroxime, ceftriaxone, cefotaxime H. influenzae: ceftriaxone, cefotaxime Moraxella catarrhalis: cefuroxime P. aeruginosa: ceftazidime, cefepime S. aureus: ceftaroline Norcardia sp: ceftriaxone, cefotaxime Meningococcus: ceftriaxone, cefotaxime 31 CARBAPENEMS Include imipenem and meropenem Imipenem is always used in combination with cilastatin, an inhibitor of renal dehydropeptidase I (an enzyme which inactivates imipenem) Used in treatment of RTIs caused by many bacteria: many gram positive and gram negative bacteria, anaerobes and P. aeruginosa 32 BETA-LACTAMS: ADVERSE EFFECTS Hypersensitivity reactions Diarrhea Pseudo-membraneous colitis (broad spectrum beta-lactams) Leukopenia, thrombocytopenia (cephalosporins) Nephritis (penicillins) Seizures (high doses of penicillins) 33 FLOUROQUINOLONES Mechanism of action Inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV and thereby inhibit the replication of bacterial DNA Indications in RTIs Pneumococcus: levofloxacin, moxifloxacin, gatifloxacin H. influenzae: levofloxacin, moxifloxacin Mycoplasma & Chlamydia pneumoniae: levofloxacin, moxifloxacin Legionella sp: levofloxacin, moxifloxacin Moraxella catarrhalis: levofloxacin, moxifloxacin Gram negative bacteria: ciprofloxacin, levofloxacin Atypical mycobacteria: levofloxacin, moxifloxacin 34 FLOUROQUINOLONES: ADVERSE EFFECTS GIT: nausea, vomiting, diarrhea CNS: headache and dizziness or light-headedness. Use with caution in patients with epilepsy, may evoke seizures. Phototoxicity Hepatotoxicity Connective tissue problems – tendinitis, tendon rupture, aortic aneurysm Contraindicated in pregnancy, lactating mothers, and children under 18 years (however, ciprofloxacin can be used in children below 18 years for treatment of typhoid fever as the benefit outweighs the risk in this case) 35 TRIMETHOPRIM-SULFAMETHOXAZOLE (CO- TRIMOXAZOLE) Co-trimoxazole is a combination anti-microbial agent consisting of sulfamethoxazole (a sulfonamide) and trimethoprim Mechanism of action Sulfamethoxazole: Inhibits the synthesis of folic acid by inhibiting the enzyme dihydropteroate synthetase which is required for the synthesis of dihydrofolate from para- aminobenzoic acid Trimethoprim: Inhibits the enzyme dihydrofolate reductase, which converts folic acid to its active, coenzyme form, tetrahydrofolic acid The combination of trimethoprim with sulfamethoxazole is synergistic (reduction in mean inhibitory concentration of each drug and extension of antimicrobial spectrum) and is bactericidal 36 CO-TRIMOXAZOLE: INDICATIONS IN RTI Co-trimoxazole is effective in RTIs due to various pathogens, including: Pneumocystis jiroveci (drug of choice) Norcadia sp (drug of choice) H. influenzae S. aureus Toxoplasma sp Atypical mycobacteria Acute bronchitis 37 CO-TRIMOXAZOLE: ADVERSE EFFECTS Hypersensitivity reactions: the hypersensitivity reactions caused by sulfamethoxazole occur (they are not dose- dependent). Reactions involving the skin are very common. Drug-induced fever GIT: nausea, vomiting, glossitis, stomatitis and diarrhoea Hemolytic anemia: in patients with glucose 6-phosphate dehydrogenase deficiency due to the sulfamethoxazole Hematological: Megaloblastic anemia, leukopenia, thrombocytopenia may be reversed by administration of folinic acid (folinic acid does not enter the microorganism) 38 TETRACYCLINES Mechanism of action Bind reversibly to the 30s subunit of the bacterial ribosome and block access of the amino acyl-tRNA to the mRNA- ribosome complex at the acceptor site Inhibit protein synthesis Indications in RTIs Mycoplasma pneumoniae: doxycycline Chlamydia pneumoniae: doxycycline Legionella sp: doxycycline S. aureus: tigecycline Atypical mycobacteria: doxycycline, minocycline 39 TETRACYCLINES: ADVERSE EFFECTS Nausea, vomiting and diarrhoea Epigastric distress; irritation of the gastric mucosa. Alleviated if taken with foods. Photosensitivity Hepatotoxicity Clostridium difficile colitis and candida super- infections Staining of teeth, hypoplasia of dental enamel and abnormal bone growth in children below 8 years and in fetuses. Tetracyclines are therefore contraindicated in pregnancy and in children younger than 12 years. 40 MACROLIDES Mechanism of action Bind irreversibly to the 50S subunit of the bacterial ribosome and thereby inhibit the translocation step of protein synthesis Indications in RTIs Pneumococcus: azithromycin, clarithromycin H. influenzae: azithromycin, clarithromycin Mycoplasma pneumoniae: azithromycin, clarithromycin, erythomycin Chlamydia pneumoniae: azithromycin, clarithromycin, erythromycin Legionella sp: azithromycin, clarithromycin, erythromycin Moraxella catarrhalis: azithromycin, clarithromycin Norcadia sp: azithromycin, clarithromycin Atypical mycobacteria: azithromycin, clarithromycin 41 MACROLIDES: ADVERSE EFFECTS Abdominal pain, nausea, vomiting, diarrhea Ototoxicity, tinnitus and dizziness with high doses (especially erythromycin) Erythromycin and clarithromycin inhibit hepatic cytochrome P450 enzymes 42 VANCOMYCIN Mechanism of action Prevents the trans-glycosylation step in peptidoglycan polymerization thereby inhibiting cell wall synthesis Active against gram positive cocci (including MRSA) Indications in RTIs S. aureus Empirical therapy for neonatal pneumonia (in combination with cefotaxime) Adverse effects Fever, chills, phlebitis at the injection site, flushing, shock when administered rapidly, rashes, ototoxicity and nephrotoxicity 43 LINEZOLID Mechanism of action Inhibits of bacterial protein synthesis - blocks the formation of the 70s initiation complex by binding to 50s subunit Active against gram positive organisms and mycobacterium tuberculosis Indications in RTIs (1) S. aureus (2) Atypical mycobacteria (3) MDR-TB Adverse effects Myelosuppression, pseudo-membraneous colitis 44 CLINDAMYCIN Mechanism of action Binds to the 50S subunit of the bacterial ribosome and thereby inhibits protein synthesis Active against anaerobic bacteria and gram positive cocci Indications in RTIs Used in RTIs whose pathogens include anaerobic bacteria: (1) Aspiration pneumonia (2) Lung abscess Adverse effects Skin rashes, GIT disturbances, impaired liver function The most serious adverse effect is pseudomembranous colitis (caused by overgrowth of Clostridium difficile) 45 AMINOGLYCOSIDES Include amikacin, gentamicin, tobramycin, streptomycin, netilmicin and kanamycin Mechanism of action Inhibit bacterial protein synthesis through binding to the 30S ribosomal subunit Are bactericidal Susceptible organisms have an oxygen-dependent system that transports the drug across the cell membrane Active only against aerobic bacteria (anaerobes lack the oxygen-requiring transport system) 46 AMINOGLYCOSIDES Indications in RTIs Used in RTIs caused by gram negative bacteria (amikacin, gentamicin, tobramycin, netilmicin), Norcardia sp (amikacin), atypical mycobacteria (amikacin, streptomycin) and MDR-TB (amikacin, kanamycin) Adverse effects Ototoxicity, nephrotoxicity, neuromuscular blockade, neurotoxicity and allergic reactions 47 METRONIDAZOLE Mechanism of action Activated by sensitive organisms via a reduction to an anion radical. This highly reactive anion radical inhibits DNA synthesis, and damage DNA and proteins resulting in the organism’s death. Indications in RTIs Used in RTIs whose pathogens include anaerobic bacteria: Aspiration pneumonia Lung abscess Given in combination with beta-lactams 48 METRONIDAZOLE … CONT’D Adverse effects Nausea, vomiting, metallic taste, headache, gastro- intestinal disturbances, rash, fever, reversible neutropenia, syncope, peripheral neuropathy, seizures at high doses Contra-indications First trimester of pregnancy (potentially mutagenic) Alcohol intake (inhibits aldehyde dehydrogenase) 49 ANTI-VIRAL DRUGS Dr Sindwa Kanyimba Lecturer, Pharmacology 50 ACYCLOVIR AND VALACICLOVIR Acyclovir is guanine nucleoside analogue MOA: Phosphorylated by viral thymidine kinase then metabolised by host cell kinases to a nucleotide analogue. The nucleotide analogue then inhibits viral DNA synthesis by inhibiting DNA polymerase. Valaciclovir is a pro-drug of acyclovir Indication in viral RTIs: varicella pneumonia Adverse effects: Nausea, diarrhea, headache, tremors and delirium 51 GANCICLOVIR AND VALGANCICLOVIR Ganciclovir is an acyclic guanosine analog Requires triphosphorylation for activation monophosphorylation is catalyzed by a phosphotransferase in CMV Mechanism of action: Phosphorylated ganciclovir inhibits DNA polymerase Valganciclovir is a pro-drug of ganciclovir, and is metabolized by intestinal and hepatic esterases to ganciclovir when administered orally. Indications in viral RTIs: CMV pneumonia Adverse effects: Myelosuppression 52 FOSCARNET An inorganic pyrophosphate Mechanism of action: Directly inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase (it does not require phosphorylation for anti-viral activity) Indications in viral RTIs: CMV pneumonia Adverse effects: Hypo- or hyper-calcemia, phosphatemia, hypomagnesemia, neurotoxicity and nephrotoxicity 53 OSELTAMIVIR AND ZANAMAVIR Are neuraminidase inhibitors The influenza virus contains an enzyme neuraminidase which is essential for the replication of the virus Neuraminidase inhibitors inhibit the enzyme neuraminidase thereby preventing the release of new virions and their spread from cell to cell Indications in viral RTIs: Influenza types A and B Can be used for both prophylaxis and acute treatment They do not interfere with immune response to influenza A vaccine Adverse effects: nausea and vomiting with both; sinusitis and bronchospasm with zanamivir 54 AMANTADINE AND RIMANTADINE Mechanism of action: Inhibit the uncoating of viral RNA therefore inhibiting replication Use: Prevention & treatment of Influenza A (have no effect on Influenza B & C) The drugs do not impair the immune response to influenza A vaccine Adverse effects: anorexia, nausea and vomiting, xerostomia, urinary retention, nervousness, insomnia, lightheadedness, difficulty concentrating, ataxia, delirium, hallucinations, seizures (with high doses). Rimantadine has fewer CNS adverse effects than amantadine. 55 RIBAVIRIN (TRIBAVIRIN) A guanosine analog Mechanism of action: (1) Inhibition of synthesis of guanosine-triphosphate which leads to inhibition of nucleic acid synthesis in general (2) Specific inhibition of viral mRNA synthesis Indications in viral RTIs: RSV, influenza and parainfluenza Adverse effects When given by aerosol: Conjunctival irritation, transient wheezing and reversible deterioration in pulmonary function When given orally or IV: Dose-dependent hemolytic anemia and bone marrow suppression, headache, 56 insomnia and mood alteration PALIVIZUMAB Palivizumab is a monoclonal antibody produced by recombinant DNA technology Mechanism of action: Binds on the fusion protein (F protein) of respiratory syncytial virus (RSV), thereby inhibiting its entry into the cell It is used in the prevention of RSV RTIs in high risk infants and young children (e.g. premature infants and children with congenital heart disease) Adverse effects include upper respiratory tract infection, fever, rhinitis, rash, diarrhea, vomiting, cough, otitis media, and elevation in serum aminotransferase levels 57 REMDESIVIR Mechanism of action: Inhibits viral RNA polymerase thereby preventing viral replication Indications in viral RTIs: RSV and Covid-19 Adverse effects: nausea, vomiting, diarrhea, abdominal pain, headache and elevation in serum aminotransferase levels 58 PAXLOVID Paxlovid consists of two components: 1. Nirmatrelvir: acts by inhibiting viral protease, an enzyme that converts inert polyproteins into various functional and structural protein, that are necessary for the production of infectious viral particles. Viral replication is thereby inhibited. 2. Ritonavir: a protease inhibitor that serves to boost nirmatrelvir by inhibiting its metabolism thereby prolonging its duration of action Indication: Covid-19 Adverse effects: nausea, vomiting, diarrhea, taste changes and abdominal pain 59 ANTI-FUNGAL DRUGS Dr Sindwa Kanyimba Lecturer, Pharmacology 60 AMPHOTERICIN B Mechanism of action: Disrupts fungal cell membrane by binding to ergosterol , so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules (causing cell death ) Broad spectrum fungicidal drug Indications in RTIs: RTIs caused by Cryptococcus spp, Aspergillus sp and Candida sp Route of administration in RTIs: slow IV infusion 61 AMPHOTERICIN B: ADVERSE EFFECTS Immediate reactions (infusion–related toxicity) Fever, muscle spasm, vomiting ,headache, hypotension. Can be reduction by slowing the infusion, decreasing the daily dose and premedication with antipyretics, anti-histamines and corticosteroids. Give a test dose before giving the full dose. Slower toxicity Most serious is renal toxicity (nearly in all patients ), hypokalemia, hypomagnesaemia, impaired liver function, thrombocytopenia and anemia 62 AMPHOTERICIN B LIPOSOMAL PREPARATIONS Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing nephrotoxicity and infusion toxicity More effective More expensive 63 FLUCYTOSINE A pyrimidine analogue that is converted within the fungal cell to 5-fluorouracil (but not in human cell), which inhibits thymidylate synthetase enzyme resulting in inhibition of DNA synthesis. It is fungistatic. Synergistic with amphotericin B (amphotericin B increases cell permeability to flucytosine, allowing more flucytosine to penetrate the cell) Indications in fungal RTIs: RTI caused by Cryptococcus spp (given in combination with amphotericin B for induction therapy). Given orally or IV. Adverse effects: Nausea, vomiting , diarrhea, severe enterocolitis, reversible neutropenia, thrombocytopenia, bone marrow depression, alopecia, elevation in hepatic enzymes 64 TRIAZOLES A group of synthetic fungistatic agents with a broad spectrum of activity Include fluconazole and voriconazole MOA: (1) Inhibit the fungal cytochrome P450 enzyme, (α-demethylase), which is responsible for converting lanosterol to ergosterol (the main sterol in fungal cell membrane) (2) Inhibit mitochondrial cytochrome oxidase leading to accumulation of peroxides that cause autodigestion of the fungus Indications in RTIs: RTIs caused by Cryptococcus spp (fluconazole), Aspergillus sp (voriconazole) and Candida sp (fluconazole, voriconazole). Both drugs are given oral and IV 65 TRIAZOLES: ADVERSE EFFECTS Fluconazole: nausea, vomiting, headache, skin rash, diarrhea, abdominal pain, alopecia, hepatic impairment Voriconazole: visual disturbances, liver damage, skin reactions, nausea, vomiting, diarrhea, abdominal pains, arrhythmias, neurotoxicity Both drugs are teratogenic 66 CASPOFUNGIN Inhibits the synthesis of fungal cell wall by inhibiting the synthesis of a glucose polymer which is an important component of the fungal cell wall, leading to lysis & cell death Given by IV route only Used aspergillosis, candidiasis and pneumocystis jirovecii RTIs Adverse effects : Nausea, vomiting, flushing (release of histamine from mast cells) 67 DRUGS USED IN TREATMENT OF TOXOPLASMOSIS Dr Sindwa Kanyimba Lecturer, Pharmacology 68 DRUGS USED IN THE TREATMENT OF TOXOPLASMOSIS First line treatment: Pyrimethamine in combination with sulfadiazine (a sulfonamide) Alternative treatment: Co-trimoxazole Pyrimethamine Mechanism of action: Inhibits dihydrofolate reductase (thus inhibits the conversion of DHF to THF) Adverse effects: Megaloblastic anaemia and folate deficiency at high doses 69 END