Integrated ID 11 Module Antimycobacterial Agents_231030_185606.pdf

INTEGRATED INFECTIOUS DISEASES MODULE I PHAR 5337 Antimycobacterial Agents Louis Williams Fall 2023 Proficiencies and Learning Objectives Given the structures of any drug, deemed clinically significant and used to treat Mycobacterial Infections like Tuberculosis, our learning objectives will be:...

INTEGRATED INFECTIOUS DISEASES MODULE I PHAR 5337 Antimycobacterial Agents Louis Williams Fall 2023 Proficiencies and Learning Objectives Given the structures of any drug, deemed clinically significant and used to treat Mycobacterial Infections like Tuberculosis, our learning objectives will be: to identify the many classifications to discuss the drugs chemical structural features and physicochemical properties (e.g., solubility, stability, absorption, distribution, metabolism and elimination) and structure activity relationships (SAR) to describe metabolic pathways, active and inactive metabolites of clinically significant cell wall drugs and any possible drug/drug interactions. BIBLIOGRAPHY Medicinal Chemistry of Drugs Used to Treat Mycobacterial Infections Foye’s Principles of Medicinal Chemistry, 8th Edition Chapter 29: Pages 1190 - 1198 Mycobacterium Infections Tuberculosis(TB): Caused by Mycobacterium tuberculosis Characterized as: An acid-fast, aerobic bacillus with an unusual cell wall Symptoms: Productive cough, fatigue, night sweats Diagnosis: Identification of organism,chest X-ray, tuberculin test Other Characteristics of M. tuberculosis Multiple drug therapy is essential: MOAs involving multiple sites Difficulties encountered: Drug resistance and patient default Long term therapy is required: slow growing organisms MAC (Mycobacterium avium-intracellulare Complex): (Atypical acid fast bacilli infection common to immune compromised patients) Mycobacterial Cell Wall α- Mycolic Acid Long arm Short arm OH (CH2)23)-CH3 CH3(CH2) 17 (CH2)14 (CH2)17 COOH Classifications First Line: Isoniazid (52’) Pyrazinamide (55’) Ethambutol (67’) Rifampin (71’) Rifabutin (92’) Rifapentine (98’) Isoniazid (pKa 10.8) Properties: • • • • • • • An isonicotinic acid derivative, also know as Isonicotinic Acid Hydrazide (INH) FDA appr. 1952 Water sol. (12.5 %) Light and air sensitive Sensitive to excessive heat Has three pKa’s (pKa 2.0, 3.5 & 10.8) SAR: Any substitution at R3 will kill the activity. Small alkyl substation at R1,2 drug derivative will still be active. • Avail. In many generic dosage forms: oral solns, tabs, and injectable soln. • Commercial avail. In combo. with other AntiTB drugs (e.g., Rifampin, Pyrazinamide) • May be combined with pyridoxine to reduce peripheral neuritis Isoniazid Cont. Pharmacokinetics: • Rapidly absorbed orally, well distributed to all body fluids and tissue (including the CSF) • Antacids (especially Al+++) & food may affect or delay absorption. (Thus, take on empty stomach.) • Metabolizes primarily via acetylation • ½ life ~1- 4 hrs (depending on the patient’s rate of acetylation) • Elim. mainly in the urine, but also elim. in feces, saliva and sputum after OD dosing • Drug is a potent inhibitor of CYP 2C19 and an inhibitor of 3A4. It is also a weak inhibitor of 2C9, 2D9 and 2A6, Yet it was shown to be an inducer and inhibitor of 2E1 Isoniazid Mechanism of Action: Reviewing Fatty Acid Synthesis O OH S-ACP O CO2 O R O R S ACP OH [H] CH2 C S ACP O CH2 C S ACP O O R S ACP R H H O H O inhA -H2O R S ACP H NH2 O NH2 + N ADPR [ NAD+ ] N ADPR Active portion of NADH Chain lengthening Isoniazid (IsoNicotinic Hydrazide) Mechanism of Action: Note: “A Cell Wall Agent!” O NH-NH2 C O katG N NH N2 O2 O O O C C C O N N N O C O (Catalase peroxide) N Mn++ Prodrug O Potential acylating agents C OH N Nicotinic acid NADH N Acylated NADH not able to reduce alkene in fatty acid synthesis. C H O O NH2 N ADPR Blocks mycolic acid synthesis N OH Metabolism: (Causing hepatotoxicity) (Resulting in Hepatotoxicity) Rifamycin Antibiotics (Ansamycin class of antibiotics produced by Streptomyces mediterranei) CH3 HO CH3 CH3 21 23 CH3 CH3 CH3COO OH CH3COO O 25 CH3 HO CH3 CH3O 15 OH 1 8 CH3 HO NH CH3 OH O CH3 HO OH NH CH3 CH3O 2 CH O O 4 OH O CH3 O Rifamycin SV 3 CHO CH3 N OH O CH3 O Rifampin R = CH3 Rifapentine R = N N R (Mycobutin) •FDA appr. 1992 •Also considered an alternative to Rifampin for TB •Bioavailability in HIV-positive patients is 12 – 20 % •Rifabutin is an inducer and a substrate of CYP 3A4 but less potent than Rifampin •Elim. ½ life 28-62 hrs Rifamycin Antibiotics MOA: Inhibits DNA-dependent RNA polymerase (DDRP) through: 1. Chelation to zinc present in DDRP 2. Hydrogen bonding to enzyme through C21 and C23 OH 3. p - p Bonding between naphthalene and aromatic amino acids of DDRP CH3 CH3 HO CH3 CH3COO OH O CH3 C23 - rifamycin C O C O NH O CH CH3O H Naphalene in refamycin H OH CH3 H H H-bonding of rifamycin to DDRP C21 - rifamycin HO CH3 N N N OH O CH3 O H O O H H O H O Zn Che lation ofC1 & C8 OH to 2+ Zinc p-Bonding between rifamycin and DDRP DDRP-surface Aromatic ring in DDRP Chelation to zinc (OH at C1 and OH at C8) R Metabolism: (Rifampin) CH3 CH3 HO CH3 CH3COO OH O CH3 HO CH3 OH CH3 NH O CH CH3O CH3 Hydrolysis Still active N N R OH O CH3 N O CYP 3A4 CH3 CH3 CH3 HO HO CH3 HO CH3 OH O CH3 HO CH3 OH O CH3 NH CH3 OH CH3COO HO OH NH CH3 CH3O CH3 CH3O CH O N N N R CH3 O CHO O OH O OH O CH3 O Still active Pharmacokinetics/Physical Chemical Properties: (Rifampin) CH3 CH3 CH3 CH3 HO HO CH3 CH3COO OH O CH3 HO Air CH3 CH3 CH3COO O CH3 OH NH CH3 OH HO CH3 O CH3 NH O CH CH3O CH3O CH O N N OH O CH3 O Readily absorbed from the GI tract: Food decreases absorption of rifampin N R N N N R O O CH3 O Rifampin - Introduced in 1967 and approv. In 71’ •Reduces combination therapy from 18 to 9 months. •Half life 2 - 5hrs •CYP450 inducer(3A4 & 2C8/9/19) •Potential for hepatotoxicity and GI irritation Rifapentine - Introduced in 1950 but was approv. in 98’ •Half life 13.2 hrs.(highly bound to Plasma protein) Excreted in urine, stools, saliva, sweat & tears (red to orange color) •CYP450 inducer (3A4 & 2C8/9) •Minimal hepatic dysfunction. Prone to air oxidation Food increases absorption of rifapentine O O N Pyrazinamide(PZA) HO C NH CH2 C OH N Conjugation O N O C NH2 N N Pyrazinamidase Prodrug O C OH Metabolism N N HO C OH N Pyrazinoic acid MOA: Lowers pH of media (i.e., activity best at ~ pH = 5.4 or less) May function as an antimetabolite of NAD synthesis H H O NH2 Therapeutics: Important component of combination therapy Useful against semidormant intracellular bacilli Reduces therapy to 6 months Available in oral 500 mg. tabs. N ADPR S Ethambutol (EMB) CH2 OH C2H 5 H C NH-CH2-CH2-NH C H C2H 5 CH2 OH CH2 OH C2H 5 H C NH-CH2-CH2-NH C H C2H 5 CH2 OH CH2 OH Metabolism C2H 5 H C NH-CH2-CH2-NH C H C2H 5 CH O S Asymmetric centers CH2 OH C2H 5 H C NH-CH2-CH2-NH C H C2H 5 C OH O Inactive MOA: EMB Arabinosyl -D-Arabinofuranosyl-1-monophosphate transferase decaprenol (Note: A Cell Wall Agent) Polyarbinose in AG & LAM CP MOA: Appears to inhibit RNA synthesis, cellular metabolism, arrest of cell multiplication, and cell death. Available as oral tabs 100, 400 mgs Side Effect: Optic neuritis with loss of visual acuity (loss of differentiation of red from green)