Pharmacology II Exam 4 PDF

Intro to Drug/Antimicrobial Therapy 1. Drug therapy a. Use of drugs to eradicate a parasite with minimal harm to the host organism b. “Parasite” may include any organism living in or on the host, including viruses, bacteria, fungi, and protozoa....

Intro to Drug/Antimicrobial Therapy 1. Drug therapy a. Use of drugs to eradicate a parasite with minimal harm to the host organism b. “Parasite” may include any organism living in or on the host, including viruses, bacteria, fungi, and protozoa. c. The analogy that I use is that this is like warfare – you are fighting a living enemy who can change and adapt. They change and adapt faster than their human targets. 2. Selective toxicity a. Specificity: A drug needs to be more toxic to the parasite than to the host b. Biochemical or physiological di?erences: e.g., Penicillin (host vs. parasite) c. Restricted distribution: e.g. Blood-tissue barriers e.g. – blood-brain barrier (BBB) d. Drug E?ectiveness: Related to di?erences between pathogen and host 3. Kirby-Bauer Disc DiPusion Test: a. b. Bigger the zone of inhibition, greater the ePicacy 4. Minimum Inhibitory Concentration (MIC) a. b. MBC/MIC ≤ 4: Bactericidal c. MBC/MIC > 4: Bacteriostatic d. Epsilometer (E) test: similar to this test, just diPerent testing device 5. Gram staining:  a. i. Gram positive bacteria: thick peptidoglycan layers and no outer lipid membrane 1. Multiple peptidoglycan layers ii. Gram negative bacteria: thin peptidoglycan layer and an outer lipid membrane iii. Hans Christian Gram (1882): staining technique, diPerentiate two groups of bacteria b. Gram staining: four basic steps i. Primary stain: crystal violet to heat-fixed smear of bacterial culture ii. Secondary stain (trapping agent): Iodine, binds to crystal violet and traps crystal violet in the cell iii. Decolorization: Ethanol or acetone iv. Counterstaining: fuchsin or safranin v. Results: 1. Gram positive = purple 2. Gram negative = pink (after washing with ethanol and counterstaining with fuchsin) 6. Role of immune response a. Response to drug: i. APected by immune response ii. Immune response aPects drug’s ability to fight infection iii. If no immune response or immune response is inePective, drugs may have to kill cells rather than just inhibit their growth and leave it to the immune system to clear the pathogen b. Absence of immune response: i. Impaired immune system – AIDS ii. Use of immunosuppressant drugs such as: 1. Cyclosporins (inhibits T-cell activation) 2. Corticosteroids iii. When the immune system is repressed, pathogen replication may be increased – which is a greater challenge for antimicrobial agents 1. In addition to increased numbers of pathogens, this may also caused increased inflammation which can lead to altered drug distribution 7. Herbal supplements  a. Some herbal supplements (ex: St. John’s Wort) may induce drug transporters (ex: P-glycoprotein) and drug metabolic enzymes (ex: CYP3A4). Echinqcea only elicits a mild response from transporters and metabolic enzymes. b. Thus, they may “induce” the immune system, but they can have a major ePect on drug metabolism and disposition. 8. Combination of drug therapy: a. Advantages i. Mixed bacterial infections ii. severe infection of unknown etiology iii. prevention of emergence of resistance in microorganisms: Tuberculosis iv. Use antibiotics that have diPerent MOAs and inhibit diPerent pathways 1. Ex: for warfare analogy – use army, navy, and air force b. Disadvantages i. Toxicity – drug-drug interactions ii. Misuse of antibiotics iii. Treatment of untreatable disease – may promote generation of resistant strains that can be spread iv. Treatment of fever of undetermined origin v. Improper dosage – consider metabolic parameters 9. Drug resistance: the biggest challenge a. By random (spontaneous) mutation b. Widespread use of antibiotics c. With Bubonic Plague (Yersinia pestis), drug resistance may (e.g. transporters, metabolic enzymes, etc) may be encoded in plasmids that can be transferred to other bacteria d. In certain viruses (e.g. HIV-1), the genome is replicated by an enzymes (reverse transcriptase) that has LOW fidelity. So, it produces a significant number of mutations during replication. e. Excessive use of antibiotics: i. f. Mechanisms of drug resistance:  i. Conjugation between 2 bacteria ii. Viral transduction iii. Transformation g. Why drug resistance? i. Increased rate of drug inactivation: Penicillinase (beta-lactamase) for bacteria ii. Altered amount or decreased aPinity of target enzyme/receptor iii. RNA polymerase (mutation) fails to bind rifampicin because the target has changed iv. Increased drug ePlux and metabolism: Drugs for TB, AIDs, etc. v. Decreased drug uptake: e.g. downregulation of porin, so drug cannot penetrate into bacteria 10. Toxicity a. Limiting factor b. Independent of therapeutic mechanisms c. Indices of Toxicity: i. Therapeutic Index (TI) 1. 2. LD50: Lethal dose of a drug for 50% of the animals 3. ED50: EPective dose for 50% of the population 4. Note: you want a big gap/wide therapeutic index between the 2 ii. % standard safety margin 1. 2. ED99 = EPective Dose causing specified ePect in 3. LD1 = Drug Dose causing death in 1% of animals 4. SSM is a more useful measure than TI Sulfonamides and Quinolones 1. Sulfonamides a. Structure and chemistry i. Basic structure of sulfonamides similar to p-aminobenzoic acid (PABA) ii. Modifications of amido or amino groups iii. More soluble at alkaline pH b. Sulfonamides: mechanism of action  i. ii. Folic acid: essential for purine and for nucleic acid synthesis iii. Bacteria: synthesize folic acid from PABA but cannot utilize exogenous folate – the opposite from humans iv. Sulfonamides, structural analogs of PABA: inhibit dihydropteroate synthetase and folic acid production v. Humans: do not make folic acid and must ingest it vi. Humans: lack the enzyme to convert PABA to folate vii. Humans: not susceptible to sulfonamides for folic acid inhibition c. Sulfonamides: resistance i. Bacterial resistance to sulfonamides may develop because of mutations in bacteria that: 1. Cause overproduction of PABA (sulfonamides compete with PABA for binding to dihydropteroate synthetase) 2. Cause production of folic acid synthesizing enzyme with low aPinity for sulfonamide 3. Impair permeability to sulfonamide d. Sulfonamides: Pharmacokinetics i. Absorbed from stomach and small intestine ii. Distributed widely to tissues and body fluids (CNS, cerebrospinal fluid, placenta, and fetus) iii. Protein binding: 20% to over 90% iv. Blood levels peak 2–6 hrs after oral administration v. Some acetylated or glucuronidated in the liver (phase II) vi. Excreted into urine, dosage reduced in renal failure e. Other folate synthesis inhibitors i. Trimethoprim or pyrimethamine: inhibitors of dihydrofolate reductase ii. may produce synergistic activity; because of sequential inhibition of folate synthesis when administered with sulfonamides f. Sulfonamides: summary of clinical uses:  i. 1. Sulfonamides are infrequently used as single agents g. Sulfonamides: adverse ePects i. Common: fever, skin rash, nausea, vomiting ii. Urinary Tract Disturbances: 1. May precipitate in urine causing renal damage 2. May need to alkalinize urine by giving sodium bicarbonate iii. Hematopoietic Disturbances 1. Hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions iv. Steven-Johnson syndrome ( 5 days 2. Higher doses 3. Elderly 4. Renal insuPiciency iii. Concurrent use with loop diuretics (furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (vancomycin or amphotericin) can: 1. Potentiate nephrotoxicity – avoid if possible n. Aminoglycosides: gentamicin i. Aminoglycoside isolated from Micromonospora purpurea ii. E?ective against both gram-positive and gram-negative organisms iii. Properties resemble those of other aminoglycosides iv. Gentamicin: antimicrobial activity 1. Gentamicin sulfate is active alone but synergistic with β- lactam antibiotics against: a. E Coli, Proteus, Klebsiella pnemoniae, Enterobater, Serratia, Stenotrophomonas, and other gram-negative rods that may be resistant to multiple other antibiotics 2. No activity against anaerobes (true of all aminoglycosides) v. Gentamicin: clinical uses 1. Intramuscular or intravenous administration a. Treat severe infections (eg, sepsis and pneumonia) caused by gram-negative bacteria (likely resistant to other drugs) b. Used in combination with a second agent, because: aminoglycoside alone may not be e?ective for infections outside the urinary tract c. Should not be used as single agent for Staphylococcal infections (resistance develops quickly) d. Aminoglycosides should not be used for single-agent therapy of pneumonia because: i. penetration of infected lung tissue poor  ii. low pH and low oxygen tension in lungs contribute to poor activity e. Gentamicin + cell wall active antibiotic for endocarditis caused by gram-positive bacteria like: streptococci, staphylococci, enterococci (synergistic killing) 2. Topical administration a. Creams, ointments, and solutions containing gentamicin sulfate for treatment of: i. infected burns, wounds, or skin lesions ii. prevention of intravenous catheter infections vi. Gentamicin: Resistance 1. Streptococci and enterococci relatively resistant (fails to penetrate the cell) 2. Gentamicin + vancomycin or penicillin: potent bactericidal ePect due to: a. Enhanced uptake of drug b. Due to inhibition of cell wall synthesis 3. Rapid resistance to gentamicin (monotherapy) in staphylococci due to selection of permeability mutants 4. Resistance commonly due to aminoglycoside-modifying enzymes in gram-negative bacteria vii. Gentamicin: adverse reactions 1. Nephrotoxicity usually reversible and mild, 5–25% receiving gentamicin > 3-5 days 2. Ototoxicity (irreversible), mainly as vestibular dysfunction 3. Ototoxicity genetic, linked to point mutation in mitochondrial DNA (1-5% patients, gentamicin >5 days) 4. Loss of hearing possible o. Aminoglycosides: Tobramycin i. Aminoglycoside from Streptomyces tenebraius ii. Antibacterial spectrum and pharmacokinetic properties similar to gentamicin iii. IM, IV, and solutions for inhalation p. Tobramycin vs Gentamycin i. Antibacterial spectrum: Few di?erences ii. Gentamicin more active against Serratia marcescens (gm-ive) iii. Tobramycin more active against Pseudomonas aeruginosa (gm-ive) iv. E. faecium can be resistant to tobramycin (gm+ive) v. Ototoxic and nephrotoxic q. Aminoglycosides: Plazomicin i. Semi-synthetic aminoglycoside recently approved ii. Treat complicated urinary tract infections iii. If alternative treatments do not work iv. May cause serious hearing, muscle or nerve problems 2. Glycopeptide antibiotics – vancomycin a. Antibiotic produced by Streptococcus orientalis and Amycolatopsis orientalis b. Active only against gram-positive bacteria (exception, flavobacterium, gm- ive) c. Glycopeptide: molecular weight 1500, water soluble and quite stable d. Vancomycin: pharmacokinetics i. Poorly absorbed from the intestinal tract ii. Administered orally only for antibiotic-associated enterocolitis caused by clostridium di?icile iii. Widely distributed in the body iv. 90% excreted by glomerular filtration v. In renal insu?iciency, accumulation may occur vi. Usually administered by slow IV infusion e. Vancomycin: mechanisms of action i. Vancomycin inhibits cell wall synthesis, binds firmly to D-Ala-D-Ala terminus of peptidoglycan pentapeptide ii. Inhibits transglycosylase, prevents further elongation of peptidoglycan and cross-linking iii. Prevents crosslinking of NAM and NAG iv. Peptidoglycan weakens, cell susceptible to lysis v. Cell membrane also damaged, which contributes to the antibacterial ePect f. Vancomycin: antibacterial activity i. Bactericidal for gram-positive bacteria ii. Kills most pathogenic staphylococci including those: 1. producing β-lactamase 2. resistant to nafcillin and methicillin (2 mcg/mL or less dose) g. Vancomycin: clinical uses i. Parenteral: bloodstream infections & endocarditis caused by methicillin-resistant staphylococci ii. Vancomycin + gentamicin: enterococcal endocarditis, who have serious penicillin allergy iii. Vancomycin + cefotaxime, ceftriaxone or rifampin for meningitis caused by a highly penicillin-resistant strain of pneumococcus iv. Clearance of vancomycin directly proportional to creatinine clearance v. Dosage reduced in patients with renal insuPiciency h. Vancomycin: Mechanisms of Resistance i. In enterococci due to: 1. modification of D-Ala-D-Ala binding site of peptidoglycan building block 2. terminal D-Ala is replaced by D-lactate i. Vancomycin: adverse reactions i. ~ 10% of cases, most reactions minor  ii. Irritating to tissue, phlebitis at site of injection iii. Chills and fever may occur iv. Ototoxicity rare and nephrotoxicity uncommon with current preparations v. Administration with another ototoxic or nephrotoxic drug, (ex: an aminoglycoside), increases risk of these toxicities (oto and nephron) vi. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL vii. More common reactions: “red man" or “red neck" syndrome (infusion-related flushing caused by release of histamine) viii. Red neck syndrome: prevented by prolonging infusion period to 1-2 hours or pretreatment with antihistamine 3. Daptomycin a. Novel cyclic lipopeptide b. Fermentation product of Stretomyces roseporus c. Spectrum of activity similar to vancomycin d. Active against vancomycin-resistant strains of enterococci & S aureus e. High molecular weight drug! f. Binds to cell membrane via calcium-dependent insertion of its lipid tail g. Depolarization of cell membrane with potassium ePlux and rapid cell death h. Renally cleared i. Skin & soft tissue infections (4mg/kg/day) j. Bacteremia and endocarditis (4mg/kg/day) k. Abnormal renal function (every other day) l. Can cause myopathy m. Should not be used to treat pneumonia n. Administered IV Erythromycin & Other Macrolides 1. Macrolides a. Chemistry i. ii. Bacteriostatic iii. Group of closely related compounds iv. A macrocyclic lactone ring (14 to 16 atoms) to which deoxy sugars are attached (1 or more) v. Erythromycin:  1. Sugars are deosamine and cladinose vi. Clarithromycin: 1. methylation of 6-OH group of erythromycin 2. prodrug, undergoes 1st pass metabolism to 14-OH clarithromycin vii. azithromycin 1. methyl-substituted nitrogen in the lactone ring viii. Sugars in clarithromycin and azithromycin are the same b. Mechanism of action of Macrolides i. Protein synthesis Inhibition: binding to the 50S subunit of 70S ribosomal complex ii. Binding to 50S subunit does not allow amino acids bound to tRNA on “P” site (aa 1-5) to join incoming aa bound to tRNA that sits on “A” site (aa # 6) iii. If aa1-5 are not joined with aa 6 – no elongation iv. Transpeptidation reaction inhibited (step 2) v. By inhibiting transpeptidation reaction (joining of aa 1-5 to aa6)/inhibits chain elongation (translation) vi. tRNA bound to the P site (t5) cannot be released vii. tRNA bound to the A site (t6) can not be translocated to the P site viii. Both P and A sites remain occupied ix. No elongation of the peptide chain x. Erythromycin also inhibits formation of 50S ribosomal subunit xi. Gm +ve accumulate 100X more macrolides than gm-ve c. Macrolides: mechanism of resistance i. Reduced permeability of cell membrane or active ePlux ii. Production of esterases that hydrolyze macrolides (Enterobacteriacae) iii. Modification of ribosomal binding site (ribosomal protection) by: 1. Chromosomal mutation 2. A macrolide-inducible or constitutive methylase 2. Erythromycin a. Erythromycin: Pharmacokinetics i. Erythromycin base is destroyed by stomach acid; must be administered with enteric coating ii. Food interferes with absorption iii. Stearates and esters: erythromycin ethylsuccinate fairly acid- resistant and somewhat better absorbed iv. Mostly metabolized in the liver v. Large amounts of administered dose excreted in bile and lost in feces, ~5% excreted in urine vi. Absorbed drug distributed widely except to brain and cerebrospinal fluid  vii. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages viii. Traverse placenta and reaches fetus ix. Serum half-life ~1.5 hrs normally; 5 hrs in patients with anuria x. Adjustment for renal failure is not necessary xi. Erythromycin not removed by dialysis b. Erythromycin: Clinical uses: i. ii. Useful as a penicillin substitute in penicillin-allergic individuals with staphylococci, streptococci, or pneumococci infections c. Erythromycin: adverse reactions i. Anorexia, nausea, vomiting, and diarrhea ii. Gastrointestinal intolerance: 1. Due to stimulation of gut motility 2. Most common reason for discontinuing erythromycin iii. Erythromycin stearate or succinate salt preferred because of less adverse reactions and better absorption iv. Erythromycins (particularly estolate – esterified form absorbed in intestine because erythromycin [non-esterified] is unstable in presence of gastric acid): a. Acute cholestatic hepatitis b. Fever, jaundice, impaired liver function c. Probably as a hypersensitivity reaction v. Other allergic reactions include fever, eosinophilia, and rashes vi. Erythromycin inhibits cytochrome P450 system 1. aPect metabolism of many drugs; 2. increases serum concentrations of digoxin (cardiac glycoside), increases its bioavailability 3. Clarithromycin a. derived from erythromycin by addition of a methyl group b. improved acid stability and oral absorption  i. compared to erythromycin c. Clarithromycin: pharmacokinetics i. Metabolized in liver ii. major metabolite 14-hydroxyclarithromycin, antibacterial activity iii. Clarithromycin and its metabolite primarily eliminated in urine iv. Dosage reduction recommended for patients with creatinine clearance less than 30 mL/min v. penetrates most tissues well, concentrations similar to or exceeding serum concentrations vi. lower incidence of gastrointestinal intolerance and less frequent dosing (compared to erythromycin) vii. Clarithro & Erythro otherwise therapeutically very similar 1. Choice usually depends upon cost and tolerability d. Clarithromycin: clinical uses i. ii. Similar antimicrobial spectrum & drug interactions as erythromycin iii. More ePective than erythromycin against Myobacterium avium complex iv. Longer half-life of clarithromycin (5-6 hrs) compared with erythromycin (1.5 hrs) permits twice-daily dosing 4. Azithromycin a. One of the world's best-selling antibiotics (Zithromax) b. 15-atom lactone macrolide ring compound i. Derived from erythromycin by addition of a methylated nitrogen into the lactone ring c. Azithromycin: pharmacokinetics i. diPers from erythromycin and clarithromycin mainly in pharmacokinetic properties ii. penetrates into most tissues extremely well 1. except cerebrospinal fluid 2. tissue concentrations exceed serum concentrations by 10- to 100-fold iii. Drug slowly released from tissues 1. Tissue half-life 2-4 days iv. Permit once-daily dosing & shortening of duration of treatment v. A single 1g dose: as ePective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis  vi. rapidly absorbed and well tolerated orally vii. does not inactivate cytochrome P450 enzymes (15-member lactone ring) 1. So fewer drug interactions d. Azithromycin: clinical uses i. ii. Azithromycin: slightly less active than erythromycin and clarithromycin against staphylococci and streptococci, and slightly more active against H influenzae 5. Fidaxomicin a. New class of narrow spectrum macrocyclic antibiotic drug b. Fermentation product obtained from actinomycete c. Bactericidal d. Inhibits bacterial RNA polymerase e. E?ective: clostridium diPicile (gram+ve) infections – currently only use for fidaxomicin Clindamycin, Chloramphenicol, and Miscellaneous Antibiotics 1. Clindamycin a. Clindamycin: mechanism of action i. A bacteriostatic antibiotic ii. bacterial protein synthesis inhibitor iii. binds to 50S rRNA of large bacterial ribosome subunit iv. inhibits aminoacyltranslocation reaction v. Also inhibits the formation of 50S ribosomal subunit b. Clindamycin: pharmacokinetics i. About 90% protein-bound ii. Penetrates well into most tissues (exceptions: brain and cerebrospinal fluid) iii. Penetrates well into abscesses, actively taken up and concentrated by phagocytic cells iv. Metabolized by liver, both parent drug and active metabolites excreted in bile and urine v. Half-life ~ 2.5 hrs in normal individuals - ~ 6 hours in patients with anuria (ex: low urine production)  vi. No dosage adjustment required for renal failure c. Clindamycin: antibacterial activity i. d. Clindamycin: clinical uses i. In combination with an aminoglycoside or cephalosporin: penetrating wounds of abdomen and gut ii. Septic abortion, pelvic abscesses, lung abscesses iii. Useful against Streptococcus pyogenes, Streptococcus pneumoniae (sensitive, but not resistant strains), Staphylococcus aureus (MSSA and MRSA) iv. Skin and soft tissue infections – esp. for patients allergic to beta- lactams v. Respiratory tract infections – lung abscess vi. Good bone penetration – osteomyelitis vii. Clindamycin plus primaquine: e?ective alternative to trimethoprim-sulfamethoxazole 1. for Pneumocystis jiroveci pneumonia in AIDS patients viii. Clindamycin in combination with pyrimethamine 1. for AIDS-related toxoplasmosis of brain e. clindamycin: resistance i. Resistance to clindamycin (generally cross-resistance to macrolides) due to: 1. mutation of the ribosomal receptor site 2. modification of receptor by a constitutively expressed methylase 3. enzymatic inactivation of clindamycin f. clindamycin: adverse ePects i. Common adverse ePects: diarrhea, nausea, skin rashes ii. Impaired liver function (with or without jaundice) and neutropenia (sometimes) iii. Severe diarrhea and enterocolitis iv. Risk factor for diarrhea and colitis 2. Chloramphenicol a. Chloramphenicol: chemistry i. Crystalline chloramphenicol: neutral, stable compound  ii. Soluble in alcohol but poorly soluble in water b. Chloramphenicol: mechanism of action i. A potent inhibitor of microbial protein synthesis ii. Binds reversibly 50S subunit of bacterial ribosome iii. Inhibits peptidyl transferase step of protein synthesis iv. A bacteriostatic broad-spectrum antibiotic c. Chloramphenicol i. Oral formulations not available in US since 1991 because of adverse ePects ii. Ophthalmic formulations and IV are still used, BUT ONLY WHEN DEEMED NECESSARY (ex: no other viable alternatives) d. Chloramphenicol: pharmacokinetics i. Widely distributed to virtually all tissues and body fluids, including CNS and cerebrospinal fluid ii. Concentration in brain tissue may be equal to that in serum iii. Drug penetrates cell membranes readily e. Chloramphenicol: antimicrobial activity i. ii. Used topically in treatment of eye infections because of broad spectrum penetration into ocular tissues f. Chloramphenicol: resistance i. Low-level resistance to chloramphenicol by selection of mutants that are less permeable to the drug ii. Clinically significant resistance due to production of chloramphenicol acetyltransferase (inactivates the drug) iii. This enzyme covalently attaches an acetyl group from acetyl-CoA to chloramphenicol, which prevents chloramphenicol from binding to ribosomes g. Chloramphenicol: adverse reactions i. Bone marrow disturbances: 1. Dose-related reversible suppression of red cell production (dosages > 50 mg/kg/day after 1-2 weeks) 2. Aplastic anemia (1 in 24,000 to 40,000; idiosyncratic reaction unrelated to dose), tends to be irreversible and can be fatal ii. Toxicity for newborn infants:  1. Newborn infants lack e?ective glucuronic acid conjugation mechanism for degradation and detoxification of chloramphenicol 2. Infants doses above 50 mg/kg/d, drug may accumulate, 3. resulting in gray baby syndrome 4. Vomiting, flaccidity, hypothermia, gray color, shock, and collapse h. Miscellaneous Antibiotics i. Metronidazole 1. Nitroimidazole drug 2. Treat infections caused by bacteria or parasites 3. Potent antibacterial activity against anaerobes 4. Selectively absorbed by anerobic bacteria and sensitive protozoa 5. Once taken up by anaerobes, it is nonenzymatically reduced 6. Metabolites of metronidazole are taken up by bacterial DNA forming unstable molecules 7. Because reduction of metronidazole usually happens only in anaerobic cells, it has little ePect on human cells or aerobic bacteria 8. Treatment of anerobic or mixed intra-abdominal infections ii. Mupirocin 1. Natural substance produced by Pseudomonas fluorescens 2. Topical application 3. Active against gram-positive cocci 4. Used to treat certain skin infections (impetigo) 5. Inhibits Staphylococcal isoleucyl tRNA synthetase iii. Nitrofurantoin 1. Bactericidal for many gram-positive & gram-negative bacteria 2. P aeruginosa and many strains of Proteus inherently resistant 3. Antibacterial activity: rapid intracellular conversion to highly reactive intermediates by bacterial reductases 4. Intermediates react nonspecifically with many ribosomal proteins 5. Disrupt metabolic processes and synthesis of proteins, RNA & DNA iv. Chlorohexidine 1. Used to treat gingivitis 2. Helps reduce inflammation and swelling of gums 3. Reduces gum bleeding 4. Gingivitis is caused by bacteria 5. Does not prevent plaque Antiprotozoal Drugs 1. Relevance of antiprotozoal drugs a. Malaria has been “eradicated” in the US since the arly 1950’s b. In 2020 – 241 million cases and 627,000 deaths c. Important for travelers to south America, Africa, parts of Asia (MOST relevant for pharm practice in KC) 2. 4 types of Malaria a. Single round of liver cell invasion & multiplication (eradicate erythrocytic stage) i. Plasmodium falciparum ii. Plasmodium malariae b. Dormant hepatic stage (eradicate erythrocytic and hepatic stages) i. Plasmodium vivax ii. Plasmodium ovale 3. Life cycle of plasmodia a. i. Parasite travels in through the bloodstream, and infects the liver or tissue ii. Forms schizonts, which are infected cell which have multiple progeny iii. Once those cells multiply to a certain point, they burst and empty into the blood, and infect red blood cells iv. Red blood cells can then keep going on with falciparum and malariae, continually generating gametocytes v. Gametocytes can be taken up as blood by another mosquito bite vi. In the mid-gut of the mosquito, the gametocytes form an oocyst, and then it can be injected into another person 4. 4-aminoquinolones – chloroquine a. Drug of choice: non-resistant* forms of Plasmodia b. EPective blood schizonticide & gametocide (not gametocidal for Plasmodium falciparum) c. Plasma T1/2 = 3-5 days d. Completely and rapidly absorbed by GI tract e. Max plasma conc. = 3 hrs f. Widely distributed in all tissues  g. Slow release from tissue and slow metabolism of drug – long half life h. *Chloroquine has been removed from some markets because of resistant parasites i. Chloroquine: clinical use i. Used for treating active infections and also prescribed for prophylaxis ii. Used against non-falciparum and non-resistant falciparum iii. Primaquine or Tafenoquine must be used for cure of dormant liver form of P. vivax and P. ovale. Good example of combination therapy j. Chloroquine: mechanism of action i. 1. Causes heme toxicity to parasite 2. Block conversion of hem to hemozoin k. Chloroquine: adverse ePects i. Common: pruritus among Africans ii. Rare: Hemolysis during G6PD Deficiency, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, hair bleaching, hypotension iii. LONG TERM (For Rheumatoid Patients) irreversible ototoxicity, retinopathy, myopathy and peripheral neuropathy l. Chloroquine contraindications i. NO during psoriasis ii. NO in case of retinal and visual field abnormalities and myopathy iii. CAUTION in case of liver, neurological and hematological disorders. iv. Antidiarrheal kaolin, Ca++, Mg++ antacids interfere with the absorption of chloroquine v. Safe during pregnancy 5. Mefloquine a. Potent blood schizonticide, Quinoline class of drug b. Can be used for chloroquine-resistant parasites c. Commonly used for prophylaxis as well as treatment of active infections d. Rare resistant cases (cross resistance with quinine but not chloroquine) e. Side ePects: i. Nausea, abdominal pain, dizziness ii. Sleep & behavioral disturbances f. Contraindications: i. Co-administration with Quinine or Quinidine ii. Patients with seizures, psychoses, arrhythmias  g. MOA – not clear, may target ribosome of plasmodium h. Generally considered safe during pregnancy 6. Primaquine a. 8-aminoquinolines class of drug b. Along with Tafenoquine, only agents e?ective against hepatic (liver) stages of P. vivax and P. ovale (as well as other Plasmodium spp.) c. P. vivax is the predominant parasite in the Americas, representing 75% of malaria cases (according to WHO) d. MOA: not known; EPective gametocide for all Plasmodial forms e. Sometimes used in chemoprophylaxis f. Adverse ePects: i. Nausea, headaches, abdominal pain ii. Rare – arrhythmias, agranulocytosis, leucopenia g. Contraindications: i. Patients with G6PD deficiency – testing required ii. Pregnancy 7. Tafenoquine a. Received approval in USA -2018 b. Used for prophylaxis and radical cure of P. vivax c. Half life of approximately 2 weeks allows cure of P. vivax with one dose – used ONLY in conjunction with Chloroquine d. MOA unclear e. Also used for prophylaxis of P. vivax i. Daily for 3 days, then weekly, then once after return ii. Also used OFF LABEL for P. ovale* f. Contraindication – same as primaquine - Patients with G6PD deficiency (testing required) – can cause severe hemolytic anemia g. *With similar in vivo response of P. ovale to primaquine to that of P. vivax, CDC subject matter experts are extrapolating the use of tafenoquine to P. ovale. 8. Mnemonic a. Plasmodium vivax b. Plasmodium ovale c. If the species has a “v” in the name, you need to eliminate dormant parasites from the liver d. Need to eradicate erythrocytic AND hepatic forms e. If you have the “V” you need the “P” (primaquine) or the “T” (Tafenoquine) 9. Artemisinin a. Active component of Chinese herbal (Qinghaosu) medicine for 2000 years b. Insoluble, can be used orally c. Analogs have been designed with improved anti-malarial ePicacy d. Can not be used chemoprophylaxis e. Irreversible neurotoxicity in animals f. Should be avoided during pregnancy part of combination therapy  g. Artemisinin Derivative – Arthemether/Lumefantrine i. Lipid soluble ii. Oral, IM and rectal administration iii. Peak plasma level 1-2 hr iv. Half life 3 hrs (oral route) v. Active only against blood stage vi. Anti-malarial activity due to free radical production vii. Multi-drug resistant malaria – not to be used in monotherapy 10. Vaccines a. No vaccines are currently available in the US b. WHO recommends that children in Africa be vaccinated with one of two vaccines that have been introduced since 2021 (RTS,S/AS01 or R21/Matrix-M) c. Both vaccines are protective against P. falciparum 11. Information for travelers a. Mefloquine, doxycycline, chloroquine, hydroxychloroquine, or Malarone may be prescribed for travelers to areas where malaria is endemic. b. Treatment may begin 2 wks before travel and last up to 1 month after return c. Preventive medications also recommended for pregnant women (ex: chloroquine) Antimycobacterial Drugs 1. Tuberculosis a. Mycobacterium tuberculosis: In humans, NOT in soil or other animals b. After two weeks of therapy – no longer contagious c. Many people recover from infection w/o therapy and disease goes into remission active Tb vs inactive (latent) infection d. Latent infection (i.e. inactive) – not transmissible e. Most infections are inactive. Many infections are inactive and accompany immigrants from developing countries f. Susceptible – older, malnutrition, HIV – 6% of those with TB test positive for HIV in the US – the rate of co-infection is MUCH higher in other countries g. MDR Tb – high mortality – 40-60% 2. Mycobacterial wall a. 1. Outer lipids 2. Mycolic acid  3. Polysaccharides (arabinoglycan) 4. Peptidoglycan 5. Plasma membrane 6. Lipoarabinomannan (LAM) 7. Phosphatidylinositol mannoside 8. Cell wall skeleton 3. Treatment a. First line of treatment (initial therapy usually beings with these 4 drugs until susceptibility of the isolate has been determined): i. Isoniazid (INH) ii. Rifampin (or other rifamycin) iii. Pyrazinamide (PZA) iv. Ethambutol (Eth) b. MDR (multi-drug resistant) – Mtb that is no longer killed by 2 first line drugs – INH and rifampin c. XDR – extensively drug resistant – MDR strain that is also resistant to fluoroquinolones and one injectable drug (kanamycin, capreomycin, amikacin) 4. General principles for many infectious diseases a. Pathogens can mutate to generate resistance b. Combination therapy often provides best results – synergy between drugs c. Monotherapy is more susceptible to failure – esp. in HIV and TB d. Anything that reduces drug levels in relevant biological compartments can possibly promote generation of resistance 5. Isoniazid (INH) a. Most active drug against non-resistant strains (ex: NOT MDR and XDR TB) b. Tablet, syrup and injectable forms c. Small molecule (137) and water soluble d. Similar in structure to pyridoxine (Vitamin B6) e. In vitro bactericidal for most (0.2mcg/ml) f. Active against extracellular as well as well as intracellular bacteria g. INH: MOA i.  h. INH: resistance i. Mutations resulting in over-expression of inhA* ii. Mutations in KatG iii. Mutations in KasA iv. Possibility of a mutant 1 in 10^6 (single drug), 1 in 10^12 (2 drugs) i. INH: pharmacokinetics i. Fast absorption in GI Tract ii. Metabolism by acetylation; liver N-acetyl transferase iii. Excretion mainly through urine iv. Half life 3 hours in slow acetylator, 1 h in rapid acetylators j. Variations in slow acetylator phenotype: i. Slow acetylator = risk for neuropathy ii. Rapid acetylator = risk for drug resistance k. INH: toxicity i. Isoniazid-induced hepatitis ~ 1% overall age=dependent rarely ii. Peripheral neuropathy rare with 300 mg dose; 10-20% with higher dose, more common in AIDS (avoid stavudine- NRTI- rarely used because of ADR), malnourishment, Diabetes, Slow acetylators. Responds to pyridoxine. iii. CNS toxicity very rare 6. Rifampin a. A derivative of Rifamycin (Streptomyces mediterranei) b. Bactericidal against M. tuberculosis and M. leprae c. Monotherapy promotes drug resistance d. No cross resistance with other class antimicrobials e. Cross resistance with Rifamycin derivatives (rifabutin, rifapentine) f. Rifampin: mechanism, resistance and pharmacokinetics i. ii. Binds the beta subunit of bacterial RNAP (RNA polymerase) iii. Di?uses in most tissues and macrophages iv. Metabolized in liver and secreted in bile g. Rifampin: toxicity i. Orange urine but harmless, sweat, tears ii. Flu-like syndrome 1% iii. Liver toxicity (cholesterol jaundice or hepatitis) but LESS toxic than INH iv. Induction of CYP pathway and therefore increases metabolism and secretion of other drugs like methadone, PI, NNRTI etc. h. Drug interactions:  i. ii. Rifampin induces CYP3A4 iii. Administration of rifampin can cause reduced levels of NNRTI/PI iv. Administration of NNRTI/PI can cause reduced levels of rifampin v. HIV + TB = DDI 7. Ethambutol a. Synthetic water soluble and stable b. In vitro 1-5 mcg/ml inhibits mycobacteria c. Inhibits polymerization of arabinoglycan – a cell wall component d. Inhibits arabinosyl transferase encoded by emb e. Over-expression of emb —> resistance f. Retrobulbar neuritis = visual activity g. Contraindicated in children h. Pharmacokinetics i. Oral—good absorption ii. Distribution – wide iii. Metabolism – half-life 2-4 hours iv. Excretion – 75% unchanged – prolonged in renal disease 8. Pyrazinamide a. Inactive at neutral pH but works at pH 5.5 so functional in lysosome b. Inhibits mycob. At 20 mcg/ml c. Mechanism unknown – i.e. EXACT MECHANISM UNK. d. Resistance- mutation in pncA (encodes pyrazinamidase) e. Note that there is a di?erence between pyridoxine and pyrazinamide f. Hepatotoxicity i. Nausea, vomiting, fever ii. Does not increase toxicity with INH/Rifampin @ TB doses 9. Streptomycin a. Aminoglycoside class of antibiotic b. 1st antibiotic for treatment of tuberculosis c. Binds to 16S rRNA of bacterial ribosome (i.e. part of 30S ribosomal subunit) d. Used as injectable drug e. NOT FOR PREGNANT PATIENTS f. Used in combination to avoid resistance g. No longer 1st line drug i. Side ePects = ototoxic and nephrotoxic 10. Recommended duration of therapy:  a. 11. First line drugs and targets (review) a. Isoniazid— Mycolic acid b. Rifamycins- RNA polymerase (RIFAMPIN-1st line) c. Ethambutol- Arabinoglycan synthesis (cell wall) d. Pyrazinamide- Unknown 12. Second line Drugs a. Ethionamide i. INH class of drugs 1. Inhibits mycolic acid synthase ii. Water solubility poor, oral iii. Metabolism in liver iv. Pyridoxine can overcome neuro. Symptom b. Capreomycin i. Protein synthesis inhibitor isolated from Streptomyces capreolus (i.e. targets ribosome) ii. Nephrotoxic and ototoxic iii. Contraindicated in pregnancy iv. Used for strep. resistant Mtb c. Cycloserine i. Inhibitor of cell wall synthesis (peptidoglycan) ii. Secreted through urine iii. Nephron and ototoxic iv. Peripheral neuropathy and CNS toxicity; Pyridoxine is recommended d. Aminosalicyclic acid i. A folate synthesis antagonist; blocks folic acid synthesis; specific against M. tuberculosis ii. GI irritation, peptic ulceration iii. Hepatosplenomegaly, hepatitis, joint pain within 3-8 weeks iv. Pregnancy – unknown e. Rifabutin i. Related to Rifampin ii. Active against M. tuberculosis, M. avium iii. Cross resistance with rifampin  iv. Less potent inducer of CYP450 therefore recommended in HIV patients v. Need to be aware of whether patient is treated with PI/NNRTI for HIV-1 f. Amikacin i. Used for multidrug-resistant TB ii. Binds to 30S ribosomal subunit iii. No cross resistance to streptomycin, but kanamycin resistant strains are often resistant to amikacin iv. MUST be used in combination with other drugs to which the Mtb is sensitive v. Administered IM or IV vi. ADR – nephrotoxicity – measure creatinine clearance g. Linezolid i. Used in combination with other second line drugs ii. Should ONLY be used for MDR TB iii. Can be administered orally iv. Binds to 50S ribosomal subunit – may block initiation v. Does not inhibit or induce CYP450 vi. ONLY used in combination therapy vii. Significant adverse e?ects – bone marrow suppression, irreversible neuropathies h. Rifapentine i. Rifampin analog ii. Inhibits RNA polymerase iii. Cross resistance to rifampin iv. SHOULD NOT be used to treat patients with HIV infection who are receiving ART v. Inducer of CYPs i. Bedaquiline i. Used ONLY for TB resistant to both rifampin and isoniazid ii. Used ONLY in combination with at least 3 other drugs to which the infection is sensitive iii. Plasma concentrations increased when taken with a high fat meal iv. Half life of bedaquiline and its metabolite (which is less active) is 5.5 months – sequestered in tissue v. CYP3A4 DDI vi. Contraindication – arrhythmia vii. MOA- inhibits mycobacterial ATP synthetase viii. Drug of last resort – only for those who absolutely need it. Unexplained mortality associated with drug. j. Fluroquinolones i. Used to treat MDR TB ii. ALWAYS used in combination with other drugs 13. Monitoring EPicacy a. Clinical improvement—10-14 days b. Sputum AFB (acid fast bacilli) i. Q 2 weeks until negative c. Sputum cultures i. Monthly until negative ii. Continue treatment at least 3 months beyond 1st negative culture 1. Consult a TB expert if pt remains symptomatic or has + cultures at 3 months 2. If positive > 4 months, suspect RESISTANCE