Pharmacology III - Lecture 3 PDF

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Protein Synthesis Inhibitors...

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Protein Synthesis Inhibitors Lecture(3)  Bacterial protein synthesis is the process by which bacteria generate proteins, which are essential for their growth, survival, and function. This process involves the translation of genetic information encoded in messenger RNA (mRNA) into functional proteins using ribosomes, transfer RNA (tRNA), and various enzymes.  A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Most of these agents exhibit bacteriostatic activity. Bacterial ribosomes are composed of 30S and 50S subunits differing from mammalian ribosomes (40S and 60S subunits). In general, selectivity for bacterial ribosomes minimizes potential adverse consequences encountered with the disruption of protein synthesis in mammalian host cells. However, high concentrations of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with mitochondrial mammalian ribosomes.  Tetracyclines Tetracyclines consist of four fused rings with a system of conjugated double bonds. S u bst i t u t i o n s o n t h e s e r i n g s a l te r t h e i n d i v i d u a l pharmacokinetics and spectrum of antimicrobial activity. v Mechanism of action Tetracyclines enter susceptible organisms via passive diffusion and by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane. Tetracyclines concentrate intracellularly in susceptible organisms. The drugs bind reversibly to the 30S subunit of the bacterial ribosome (bacteriostatic). This action prevents binding of tRNA to the mRNA–ribosome complex, thereby inhibiting bacterial protein synthesis.  Tetracyclines v Antibacterial spectrum The tetracyclines are broaad-spectrum bacteriostatic antibiotics effective against a wide variety of organisms, including gram-positive and gram- negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. They are commonly used in the treatment of acne and Chlamydia infections. Demeclocycline reduces the sensitivity of V2 receptors to vasopressin (ADH) for the management of syndrome of inappropriate antidiuretic hormone secretion (SIADH).  Tetracyclines v Resistance The most commonly encountered naturally occurring resistance to tetracyclines is an efflux pump that expels drug out of the cell, thus preventing intracellular accumulation. Other mechanisms of bacterial resistance to tetracyclines include enzymatic inactivation of the drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome. Resistance to one tetracycline does not confer universal resistance to all tetracyclines, and the development of cross-resistance may be dependent on the mechanism of resistance.  Tetracyclines v Pharmacokinetics 1. Absorption Tetracyclines are adequately absorbed after oral ingestion. A d m i n i st rat i o n w i t h d a i r y p ro d u c t s o r o t h e r substances that contain divalent and trivalent cations (for example, magnesium, calcium and aluminum antacids, or iron supplements) decreases absorption, particularly for tetracycline, due to the formation of nonabsorbable chelates. Both doxycycline and minocycline are available as oral and intravenous (IV) preparations.  Tetracyclines v Pharmacokinetics 2. Distribution The tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin. Moreover, they bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have high calcium content. Penetration into most body fluids is adequate. Only minocycline and doxycycline achieve therapeutic levels in CSF. Minocycline also achieves high concentrations in saliva and tears, rendering it useful in eradicating the meningococcal carrier state. All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition. 3. Elimination Tetracycline is primarily eliminated unchanged in the urine, whereas minocycline undergoes hepatic metabolism and is eliminated to a lesser extent via the kidney. Doxycycline is the safest in patients with renal dysfunction, as it is primarily eliminated via the bile into the feces.  Tetracyclines v Adverse effects 1. Gastric discomfort Tetracycline should be taken on an empty stomach. Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible for noncompliance with tetracyclines. Esophagitis may be minimized through coadministration with food (other than dairy products) or fluids and the use of capsules rather than tablets. 2. Effects on calcified tissues Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth. For this reason, the use of tetracyclines is limited in pediatrics.  Tetracyclines v Adverse effects 3. Hepatotoxicity Rarely hepatotoxicity may occur with high doses (due to enterohepatic circulation). 4. Phototoxicity Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. This toxicity is encountered with any tetracycline, but more frequently with tetracycline and demeclocycline. Patients should be advised to wear adequate sun protection. 5. Vestibular dysfunction Dizziness, vertigo, and tinnitus may occur particularly with minocycline, which concentrates in the endolymph of the ear and affects function.  Tetracyclines v Adverse effects 6. Pseudotumor cerebri Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Although discontinuation of the drug reverses this condition, it is not clear whether permanent sequelae may occur. v Contraindications The tetracyclines should not be used in pregnant or breast-feeding women or in children less than 8 years of age.  Glycylcyclines Tigecycline, a derivative of minocycline, is the first member of the glycylcycline antimicrobial class. It represents the 3rd generation tetracyclines. It is indicated for the treatment of complicated skin and soft tissue infections, complicated intra- abdominal infections, and community-acquired pneumonia. v Mechanism of action Tigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting bacterial protein synthesis.  Glycylcyclines v Antibacterial spectrum Tigecycline exhibits broad-spectrum activity that includes methicillin-resistant staphylococci (MRSA), multi-drug resistant streptococci, vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase–producing gram-negative bacteria, Acinetobacter baumannii, and many anaerobic organisms. Tigecycline is not active against Morganella, Proteus, Providencia, or Pseudomonas species. v Resistance Tigecycline was developed to overcome the emergence of tetracycline class–resistant organisms that utilize efflux pumps and ribosomal protection to confer resistance. Resistance to tigecycline has been observed and is primarily attributed to overexpression of efflux pumps.  Glycylcyclines v Pharmacokinetics Following IV infusion, tigecycline exhibits a large volume of distribution. It penetrates tissues well but achieves low plasma concentrations. Consequently, tigecycline is a poor option for bloodstream infections. The primary route of elimination is biliary/fecal. No dosage adjustments are necessary for patients with renal impairment; however, a dose reduction is recommended in severe hepatic dysfunction.  Glycylcyclines v Adverse effects Adverse effects are similar to those of the tetracyclines and include photosensitivity, pseudotumor cerebri, discoloration of permanent teeth when used during tooth development, and fetal harm when administered in pregnancy. Tigecycline is associated with significant nausea and vomiting. Acute pancreatitis, including fatality, has been reported with therapy. Elevations in liver enzymes may also occur. All-cause mortality in patients treated with tigecycline is higher than with other agents. A boxed warning states that tigecycline should be reserved for use in situations when alternative treatments are not suitable. Tigecycline may decrease the clearance of warfarin. Therefore, the international normalized ratio (INR) should be monitored closely when tigecycline is coadministered with warfarin.  Aminoglycosides Aminoglycosides narrow-spectrum antibiotics that are used for the treatment of serious infections due to aerobic gram-negative bacilli; however, their clinical utility is limited due to serious toxicities. v Mechanism of action Aminoglycosides diffuse through porin channels in the outer membrane of susceptible organisms. Inside the cell, they bind irreversibly (bactericidal)to the 30S ribosomal subunit, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code.  Aminoglycosides v Mechanism of action Aminoglycosides have concentration-dependent bactericidal activity; that is, their efficacy is dependent on the maximum concentration (Cmax ) of drug above the minimum inhibitory concentration (MIC) of the organism. They also exhibit a postantibiotic effect (PAE), which is continued bacterial suppression after drug concentrations fall below the MIC. The larger the dose, the longer the PAE. Because of these properties, high-dose extended-interval dosing is commonly utilized.  Aminoglycosides v Antibacterial spectrum The aminoglycosides are effective for the majority of aerobic gram- negative bacilli, including those that may be multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp. (UTI). Also, used in TB. Additionally, aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis. Gentamicin is the most important aminoglycoside, its main use being in the ‘empirical’ treatment of acute, life-threatening gram-negative infections (e.g. Pseudomonas aeruginosa) in hospitals, until antibiotic sensitivities are known. Amikacinis less affected by aminoglycoside-inactivating enzymes and is used in serious gram-negative infections that are gentamicin resistant.  Aminoglycosides v Resistance Resistance to aminoglycosides occurs via: 1) efflux pumps, 2) decreased uptake, and/or 3) modification and inactivation enzymes. Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance cannot be presumed. Amikacin is less vulnerable to these enzymes than other antibiotics in this group.  Aminoglycosides v Pharmacokinetics 1. Absorption The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption after oral administration; therefore, all aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum concentrations. Neomycin is not given parenterally due to severe nephrotoxicity. It is administered topically for skin infections or orally to decontaminate the gastrointestinal tract prior to colorectal surgery. Given also in hepatic encephalopathy to kill gut flora producing ammonia.  Aminoglycosides v Pharmacokinetics 2. Distribution Because of their hydrophilicity, aminoglycoside tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable. Higher doses are required in pediatrics (Why??) Concentrations achieved in CSF are inadequate, even in the presence of inflamed meninges. For central nervous system infections, the intrathecal route may be utilized. All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. 3. Elimination More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine. Accumulation occurs in patients with renal dysfunction; thus, dose adjustments are required. Neomycin is primarily excreted unchanged in the feces.  Aminoglycosides v Adverse effects Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin plasma concentrations is imperative to ensure appropriateness of dosing and to minimize dose- related toxicities. The elderly are particularly susceptible to nephrotoxicity and ototoxicity. 1. Ototoxicity Ototoxicity is directly related to high peak plasma concentrations and the duration of treatment. Deafness may be irreversible and has been known to affect developing fetuses. Patients simultaneously receiving concomitant ototoxic drugs, such as cisplatin or loop diuretics, are particularly at risk. Vertigo (especially in patients receiving streptomycin) may also occur.  Aminoglycosides v Adverse effects 2. Nephrotoxicity Retention of the aminoglycosides by the proximal tubular cells resulting in kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible acute tubular necrosis. 3. Neuromuscular paralysis This adverse effect is associated with a rapid increase in concentration (for example, high doses infused over a short period) or concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine can reverse the block that causes neuromuscular paralysis. 4. Allergic reactions Contact dermatitis is a common reaction to topically applied neomycin. Q 1 : W h i c h o f t h e fo l l o w i n g i s a c o m m o n mechanism of action for tetracyclines? A) Inhibition of DNA synthesis B) Disruption of cell wall synthesis C) Inhibition of protein synthesis by binding to the 30S ribosomal subunit D) Inhibition of RNA polymerase Q2: Which tetracycline is often preferred for patients with renal insufficiency due to its excretion primarily through the feces? A) Tetracycline B) Doxycycline C) Minocycline D) Tigecycline Q3: Which tetracycline derivative is associated with vestibular toxicity, including dizziness and vertigo? A) Tetracycline B) Doxycycline C) Minocycline D) Tigecycline Q4: What is the primary route of administration for tigecycline? A) Oral B) Intramuscular C) Subcutaneous D) Intravenous Q5: Which of the following organisms is most likely to be resistant to tetracyclines due to an efflux pump mechanism? A) Escherichia coli B) Staphylococcus aureus C) Pseudomonas aeruginosa D) Streptococcus pneumoniae Q6: Aminoglycosides exert their antibacterial effects by: A) Inhibiting cell wall synthesis B) Disrupting the bacterial cell membrane C) Binding to the 30S ribosomal subunit and causing misreading of mRNA D) Inhibiting DNA gyrase Q7: What is the main toxicity concern associated with aminoglycosides? A) Hepatotoxicity B) Nephrotoxicity and ototoxicity C) Cardiotoxicity D) Hematotoxicity Q8: Which of the following antibiotics is known for its activity against multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA)? A) Tetracycline B) Doxycycline C) Minocycline D) Tigecycline Q 9: Ami no gl yco si des exhi bi t w hi c h o f t h e following pharmacokinetic properties? A) High oral bioavailability B) Poor penetration into the CNS C) Extensive liver metabolism D) All answers are correct Q10: Which of the following is a characteristic feature of aminoglycosides' pharmacodynamics? A) Time-dependent killing B) Concentration-dependent killing C) Bacteriostatic activity D) Narrow therapeutic index with low risk of toxicity thank you