Basic Pharmacology Mod 5: Protein Synthesis Inhibitors PDF

BASIC PHARMACOLOGY 09/05/2024. MOD 5: PROTEIN SYNTHESIS INHIBITORS...

BASIC PHARMACOLOGY 09/05/2024. MOD 5: PROTEIN SYNTHESIS INHIBITORS Charles C. Monsada, MD Trans Groups: 7A & 8A I. PROTEIN SYNTHESIS INHIBITORS ○ GNATS: Gentamicin, Neomycin, Amikacin, Tobramycin and Streptomycin ○ NNOT: adverse effects including Nephrotoxicity, Neuromuscular blockade, Ototoxicity and Teratogen Bactericidal: irreversible inhibitors of protein synthesis by binding to 30S ribosomal unit via: ○ Interfere with initiation complex of peptide formation ○ Misreading of mRNA → nonfunctional protein ○ Breakup of polysomes into nonfunctional monosomes 2. MECHANISM OF RESISTANCE Production of a transferase enzyme that inactivates aminoglycoside (primally seen clinically) Impaired entry into the cell from mutation of a porin protein, aquaporins are the entry points of antibiotics inside the prokaryotic cell. Mutation on the receptor protein in 30S ribosomal subunit causing prevention/inhibition of binding. 3. PHARMACOKINETICS Summary of the events that happen during protein Aminoglycosides are absorbed poorly in the GIT synthesis. ○ Hence, aminoglycosides are given as an IV infusion in clinical settings for 30 to 60 minutes. Drugs that specifically target smaller bacterial ○ In some medications like streptomycin (for patients ribosomes (70S made of 30S and 50S subunits), with TB), the drug is given intramuscularly. leaving human ribosome 80S unaffected. Half life of aminoglycosides: 2-3 hours Traditionally,aminoglycosides are administered in 2 or 3 “Buy AT 30, CCSEL (sell) at 50” equally divided doses per day. However, depending on the clinical scenario, 30S INHIBITORS 50S INHIBITORS aminoglycosides are usually administered with a single injection for the entire daily dose. This is because of Aminoglyoside* Chloramphenicol the following reasons: Tetracyclines Clindamycin ○ Concentration dependent killing: where aminoglycosides given at a higher concentration kill Streptogramin faster and more bacteria. ○ Post-antibiotic effect: a characteristic unique to Erythromycin (Macrolides) aminoglycosides. It simply means that the antibacterial activity persists BEYOND the time that Linezolid* the drug is measurable in the blood. Synergistic killing: aminoglycosides are also usually All are bacteriostatic EXCEPT Aminoglycoside* combined with cell-wall inhibiting antibiotics (e.g., (bactericidal) and Linezolid* (variable). Beta lactams or Vancomycin), resulting in a greater effect than if either of the drugs were used individually. II. INHIBITORS OF 30S RIBOSOMAL SUBUNIT 4. ADVERSE EFFECTS A. AMINOGLYCOSIDES For adverse effects of aminoglycosides, remember the Streptomycin, Neomycin, Kanamycin, Amikacin, mnemonic NNOT: Gentamicin, Tobramycin, Sisomicin, Netilmicin and Plazomicin ADVERSE EFFECTS OF AMINOGLYCOSIDES Suffix: “—mycin or micin” DO NOT confuse with macrolide antibiotics 1. MECHANISM OF ACTION Requires oxygen for uptake (NOT effective for anaerobic infections) Mnemonic: “Mean” (aminoglycosides) GNATS caNNOT kill anaerobes Pharmacology - Mod 5 Protein Synthesis Inhibitors 1 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Nephrotoxicity Occurs when aminoglycosides are Nontuberculous infections given concurrently with drugs like: (Plague, Tularemia, ○ Vancomycin Brucellosis) ○ Amphotericin Enterococcal Endocarditis ○ Loop diuretics (e.g., furosemide, ethacrynic acid) Notes: Isolated from Streptomyces More likely to be encountered in griseus patients with therapy continued for >5 days and at high doses. Severe infections from: P. ○ Particularly in populations like aeruginosa, Enterobacter sp., the elderly and those with Serratia marcescens, Proteus renal insufficiencies. sp., Acinetobacter sp., Klebsiella The most nephrotoxic Gentamicin sp. aminoglycosides include Notes: Isolated from Neomycin, Tobramycin, and Micromonospora purpurea Gentamicin Streptococci and Enterococci are Neuromuscular Usually reversible with calcium relatively resistant blockade gluconate or neostigmine. More active against S. Ototoxicity Initial presents as tinnitus and marcescens Tobramycin high frequency hearing loss. Slightly more active against P. Can progress to vertigo, ataxia, aeruginosa and loss of balance. Proteus, Pseudomonas, Auditory damage is most likely Enterobacter, Serratia seen in patients taking Neomycin, Amikacin Kanamycin, and Amikacin. Notes: Less toxic semisynthetic Vestibular damage is most likely derivative of Kanamycin seen in patients taking Streptomycin and Gentamicin. Neomycin: only used topically Also more likely to be encountered and orally in patients with therapy continued Kanamycin: limited to the Neomycin, for >5 days and at high doses. treatment of multidrug resistant Kanamycin, ○ Particularly in populations like tuberculosis Paromomycin the elderly and those with Paromomycin: visceral renal insufficiencies. leishmaniasis (oral), cutaneous leishmaniasis (topical) Teratogen You should not prescribe this drug to pregnant women. Complicated urinary tract infection Plazomicin Newest aminoglycoside in Adverse effects from aminoglycosides are usually both this table time and concentration dependent. ○ Toxicity is unlikely to occur until a certain threshold concentration is reached. B. SPECTINOMYCIN ○ Once reached, the time beyond this threshold Aminoacyclitol antibiotic structurally related to becomes critical. aminoglycoside. Active in vitro against gram-positive and gram-negative 5. CLINICAL USE organisms. Aminoglycosides are utilized primarily for aerobic Used as an alternative treatment for drug resistant gram-negative bacteria or aerobic gram-negative gonorrhea or gonorrhea in penicillin allergic infections. patients. ○ Aminoglycosides like Amikacin are usually seen in patients with drug-resistant pathogens or those in C. TETRACYCLINES the ICU (critically-ill patients). Tobramycin and Gentamicin are always used in combination with beta lactams like penicillin. ONSET OF ACTION DRUGS ○ To extend its empirical coverage and take Tetracycline advantage of the synergism between the two drug Short-acting Oxytetracycline classes. Amikacin and Streptomycin are usually given in Demeclocycline combination with other antibiotics for mycobacterium Intermediate-acting Methacycline infection. Aminoglycosides may also be utilized for Enterococcal Doxycycline Endocarditis and Viridans Streptococcal Long-acting Minocycline Endocarditis. Tigecycline AMINOGLYCOSIDE CLINICAL USE Streptomycin Mycobacterial infections Pharmacology - Mod 5 🏠 Protein Synthesis Inhibitors 2 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Formulation of insoluble complexes with divalent (Ca2+, Mg2+) and trivalent compounds (Al3+) ○ Dairy products and antacids ○ Alkaline pH In some cases, dairy products, antacids, and alkaline pH halt the absorption of tetracycline. Therefore, it is important to advise patients to avoid these food products while taking oral tetracycline. Tetracycline structure. 4.1 Distribution 1. MECHANISM OF ACTION Wide distribution to tissues and body fluids (except Bacteriostatic: bind to the 30s ribosomal subunit → CSF) blocking the binding of the aminoacyl-tRNA to the Crosses the placenta and excreted in milk acceptor site on the mRNA-ribosome complex → ○ It may also cause an effect primarily in the growing prevent the addition of amino acid in the peptide → fetus halted formation of the peptide chain and inhibited ○ NOTE: Avoid giving Tetracycline in pregnant formation of the complete protein patients. 4.2 Metabolism Doxycycline: half-life shortened by 50% by induction of hepatic enzymes by carbamazepine, barbiturates (anti-seizure), phenytoin, chronic alcohol intake 4.3 Excretion Mainly excreted in bile and urine Some of the drug excreted in bile is reabsorbed in the intestine Doxycycline and tigecycline — eliminated by non-renal mechanism → no dose adjustment in renal failure 5. CLINICAL USE Utilized in patients with: Mechanism of action. ○ Borrelia sp. (rocky mountain spotted fever and lyme disease) 2. SPECTRUM OF ACTIVITY ○ Rickettsiae Gram-positive and gram-negative (broad spectrum) ○ Mycoplasma pneumoniae Utilized primarily for: ○ Chlamydiae ○ Anaerobic infections ○ Rickettsial infections ○ Atypical microorganisms: TETRACYCLINE CLINICAL USE Chlamydiae Alternative agent for primary and Mycoplasma Doxycycline secondary syphilis 3. MECHANISM OF RESISTANCE Eradicate the meningococcal carrier Impaired influx or increased efflux by an active state. transport protein pump Minocycline However, due to resistance of ○ Most important mechanism of resistance: Tet(AE) many strains, the preferred agent and Tet(K) efflux pump is Ciprofloxacin or Rifampin. Ribosome protection due to production of proteins that Off-label use in treatment of interfere with tetracycline binding to ribosome Demeclocycline secretion of inappropriate Enzymatic inactivation of the drug itself antidiuretic hormone (SIADH) 4. PHARMACOKINETICS 5. ADVERSE REACTION Gastrointestinal Adverse Effects TETRACYCLINE ABSORPTION (Oral) ○ Nausea, vomiting, diarrhea Tetracycline, Demeclocycline 60 to 70% ○ Alteration of normal gastrointestinal flora → overgrowth of Pseudomonas, Proteus, Doxycycline, Minocycline 95 to 100% Staphylococci, Clostridia (lower for C. perfringes), Candida Tigecycline, Eravacycline Poorly absorbed orally, Incidence of Pseudomembranous colitis is given via IV. quite lower in patients taking tetracycline. Bony Structures and Teeth Portion of oral drug → remains in GIT lumen → alters ○ Readily bound to calcium deposited in bone or teeth intestinal flora, excreted in feces in young children (fluorescence, discoloration, Absorption impaired by: enamel dysplasia), and bone deformity/growth ○ Food (EXCEPT doxycycline and minocycline) inhibition Impairment in Hepatic Function ○ Hepatic necrosis ○ Renal tubular acidosis Pharmacology - Mod 5 🏠 Protein Synthesis Inhibitors 3 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Fanconi syndrome 5. ERYTHROMYCIN ADVERSE REACTION III. INHIBITORS OF 50S RIBOSOMAL SUBUNIT Gastrointestinal upset: most common adverse reaction of erythromycin A. MACROLIDES ○ Anorexia Macrolides have the suffix -thromycin. For example, ○ Nausea Erythromycin, Clarithromycin and Azithromycin. ○ Diarrhea Hepatic Toxicity: Acute Cholestatic Hepatitis 1. MECHANISM OF ACTION Hypersensitivity reaction Bacteriostatic Metabolite inhibits cytochrome P450 enzymes → Inhibition of protein synthesis occurs via binding at 50s increased amount of drugs being metabolized by the rRNA → binding at peptidyl transferase center → cytochrome P450 enzymes peptide chain elongation inhibition MACROLIDE CLINICAL USE SPECTRUM OF ACTIVITY Mycobacterium avium complex Pneumococci Mycobacterium leprae Streptococci Toxoplasma gondii Gram Positive H. influenzae Staphylococci Corynebacteria Clarithromycin Notes: Neisseria Improved acid stability and oral Bordetella pertussis absorption Gram Negative Lower incidence of Bartonella henselae B. quintana gastrointestinal intolerance Mycoplasma M. avium complex Legionella T. Gondii Chlamydia trachomatis Chlamydia sp. C. psittaci Other species Notes: C. Chlamydophila pneumoniae H. pylori Less active against staphylococci, Listeria monocytogenes more active with H. influenzae Mycobacteria spp. Usually utilized as a treatment for atypical pneumonia. Azithromycin Elimination half-life: 3 days → may 2. MECHANISMS OF RESISTANCE be given as a once a day dose, Reduced permeability of cell membrane or active short course, or once a day for 3 efflux days (in some cases) Production of esterases that hydrolyze macrolides In terms of the compliance of the (Enterobacteriaceae) patient, when given Azithromycin, it Modification of the ribosomal binding site is actually better compared to Efflux and methylase / esterase production: most when given other types of important resistance mechanism primarily on gram antibiotics which has 3 or 2 times a positive organisms. day dosing. Cross-resistance can also occur between different groups of macrolides Clostridium difficile ○ Eg. resistance against Erythromycin may also cause resistance in other macrolides Notes: (Clarithromycin, Azithromycin, etc.) Fidaxomicin Only used as a treatment for Clostridium difficile infection, 3. PHARMACOKINETICS specifically Pseudomembranous Destroyed by stomach acid → Enteric coating is colitis. needed Community acquired bacterial Food interferes with absorption (given at an empty pneumonia stomach) NO adjustments for renal failure Notes: All macrolides are concentrated in the liver (dosage Only used in the US as a treatment lowered in patients with liver disease) for community acquired bacterial May cross the placenta Ketolides pneumonia. (Telithromycin) Removed from the US because of 4. ERYTHROMYCIN CLINICAL USE cases of hepatitis and liver Erythromycin: prototype drug failure. Drug of choice for: Contraindicated for patients with ○ Corynebacterial infection Myasthenia gravis because it may ○ Chlamydial infection exacerbate their conditions. ○ Community-acquired pneumonia Substitute in penicillin allergic patients with susceptible staphylococci, streptococci, pneumococci B. LINCOSAMIDES Prophylaxis against endocarditis at dental procedures in patients with valvular disease 1. CLINDAMYCIN Legionnaire’s disease Only antibiotic in Lincosamides Pharmacology - Mod 5 🏠 Protein Synthesis Inhibitors 4 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Chlorine substituted derivative of lincomycin (from 2. CLINICAL USE Streptomyces lincolnensis) Bacterial meningitis: alternative to beta lactam antibiotic in patients who have hypersensitivity reaction 2. MECHANISM OF ACTION ○ Used in patients with bacterial meningitis because Bacteriostatic: interferes with formation of initiation Chloramphenicol can cross the blood brain barrier complexes and aminoacyl translocation reaction → Rocky mountain spotted fever inhibition of protein synthesis 3. ADVERSE EFFECT 3. CLINICAL USE Aplastic anemia: rare consequence and dose Primarily used for anaerobic infections (Bacteroides dependent spp., Clostridium perfringens) in aspiration pneumonia, Anemia: dose dependent — at dosage above 50 lung abscess, and oral infection mg/kg/day after 1-2 weeks Effective against group A streptococcal infection Gray baby syndrome: most notable effect of Anaerobic infections occurring above the diaphragm — Chloramphenicol administer Clindamycin ○ Primarily in premature infants because they lack Anaerobic infections occurring below the diaphragm — UDP-glucuronyltransferase administer Metronidazole E. OXAZOLIDINONES 4. ADVERSE EFFECT Pseudomembranous colitis (C. difficile overgrowth) 1. LINEZOLID — diarrhea and colitis specifically for hospitalized Inhibits protein synthesis by binding to the 50s subunit patients and preventing the formation of the initiation Impaired liver function complex Neutropenia Diarrhea, Nausea 2. CLINICAL USE Skin rash For gram-positive species including Methicillin-resistant Staphylococcus aureus (MRSA) and C. STREPTOGRAMINS vancomycin-resistant enterococci (VRE). 1. QUINUPRISTIN-DALFOPRISTIN 3. ADVERSE EFFECT Combination of two streptogramin in 30:70 ratio Principal toxicity is a hematologic defect (that may Quinupristin (Streptogramin B) cause bone marrow suppression) Dalfopristin (Streptogramin A) ○ Thrombocytopenia: most common and significant Share same ribosomal binding site as macrolides and manifestation of bone marrow suppression clindamycin Usually the adverse effects are being taught because of Inhibit protein synthesis in the same number as the inhibition of your mitochondrial protein synthesis macrolides ○ Peripheral neuropathy ○ Optic neuropathy 2. MECHANISM OF ACTION ○ Lactic acidosis (in the prolonged course in taking Bactericidal (most organisms except Enterococcus your Linezolid) faecium) F. PLEUROMUTILINS 3. CLINICAL USE Gram positive cocci 1. LEFAMULIN ○ Multidrug-resistant strains of streptococci Novel antibacterial agent approved in 2019 for treatment ○ Penicillin-resistant strains of S. pneumoniae of pneumonia ○ Methicillin-susceptible and resistant strains of First systemic agent available in the pleuromutilin staphylococci class for human use (since it was primarily used for ○ Enterococcus faecalis (Vancomycin-resistant veterinary medicine) strains) 2. MECHANISM OF ACTION 4. ADVERSE EFFECT Binds 50s ribosome → causes binding pocket to close Infusion-related events around the drug molecule → prevents bacterial ○ Pain at injection site transfer RNA (tRNA) from binding appropriately ○ Phlebitis Bactericidal activity in organisms causing lower ○ Arthralgia-myalgia syndrome respiratory tract infection (Streptococcus pneumoniae, H. influenzae, and atypical pathogens like D. CHLORAMPHENICOL chlamydia and mycoplasma species). 1. MECHANISM OF ACTION 3. CLINICAL USE Bacteriostatic: inhibits peptide bond formation at 50s Limited for the treatment of adult patients with ribosomal subunit community-acquired pneumonia Use is limited for life threatening infections due to its toxicity 4. ADVERSE EFFECT ○ In some countries, Chloramphenicol is only Infusion-related site reactions seldomly used due to its toxic effect. Gastrointestinal disturbance ○ However, developing countries still utilize Avoided in pregnancy → increased risk for Chloramphenicol in some cases of infection due to congenital malformation (TERATOGEN) its cheap cost. Pharmacology - Mod 5 🏠 Protein Synthesis Inhibitors 5 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.