Respiratory Tract infections

PROF. AzzA ELMedany Department of pharmacology

Objectives of the lecture At the end of lecture, students should be able to understand the following: At the end of lecture, students should be able to understand the following: Types of respiratory tract infections Types of respiratory tract infections Antibiotics commonly used to treat Antibiotics commonly used to treat respiratory tract infections and their respiratory tract infections and their side effects. side effects. Understand the mechanism of action, pharmacokinetics of individual drugs. Understand the mechanism of action, pharmacokinetics of individual drugs.

The respiratory tract

Classification of respiratory tract infections Upper respiratory tract infections (URTI) Upper respiratory tract infections (URTI) Lower respiratory tract infections (LRTI) Lower respiratory tract infections (LRTI)

URTI Rhinitis- inflammation of the nasal cavity Rhinitis- inflammation of the nasal cavity Sinusitis- inflammation of sinuses Sinusitis- inflammation of sinuses Pharyngitis- inflammation of the pharynx, uvula, tonsils Pharyngitis- inflammation of the pharynx, uvula, tonsils Laryngitis- inflammation of the larynx Laryngitis- inflammation of the larynx Laryngotracheitis- inflammation of the larynx & trachea Laryngotracheitis- inflammation of the larynx & trachea Tracheitis- inflammation of trachea Tracheitis- inflammation of trachea Otitis media- inflammation of middle ear Otitis media- inflammation of middle ear

The path of air

LRTI Bronchitis Bronchitis Acute Acute Chronic Chronic Acute exacerbation of chronic bronchitis Acute exacerbation of chronic bronchitis Pneumonia Pneumonia Community -acquired Community -acquired Hospital-acquired Hospital-acquired

LRTI, s Are more costly to treat and generally more serious than URTI, s Are more costly to treat and generally more serious than URTI, s

Causes of URTI, s Viruses ( over 200 different types have been isolated ) Viruses ( over 200 different types have been isolated ) Bacteria, mainly Group A streptococcus & H. influenzae Bacteria, mainly Group A streptococcus & H. influenzae

Causes of LRTI, s Bacteria mainly: Bacteria mainly: Streptococcus pneumoniae Streptococcus pneumoniae Haemophilus influenzae Haemophilus influenzae Moraxella catarrhalis Moraxella catarrhalis

Lines for treatment of respiratory tract infections Analgesics ( NSAIDs) Analgesics ( NSAIDs) Nasal decongestant Nasal decongestant Vitamin C Vitamin C Drinking plenty of fluids Drinking plenty of fluids Antiviral Antiviral Antibiotics Antibiotics

Antibiotics First-line treatment ( given for 3-10 days) For the treatment of moderate to severe infections For the treatment of moderate to severe infections Broad spectrum penicillins Broad spectrum penicillins Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Tetracyclines ( doxycycline ) Tetracyclines ( doxycycline )

Antibiotics ( continue) Second-line treatment Second-line treatment Used in allergic patients to drugs of first – line or in antibiotic –resistant organisms Used in allergic patients to drugs of first – line or in antibiotic –resistant organisms Macrolids Macrolids Cephalosporins Cephalosporins Fluoroquinolones Fluoroquinolones

Penicillins

Mechanism of action Inhibits bacterial cell wall synthesis Inhibits bacterial cell wall synthesisBactericidal

Pharmacokinetics  Given orally or parnterally  Not metabolized in human.  Relatively lipid insoluble.  Excreted mostly unchanged in urine.  Half-life min ( increased in renal failure).

Adverse effects Hypersensitivity reactions Convulsions ( after high dose by IVI or in renal failure) Nephritis Diarrhea Superinfections

Broad- spectrum penicillins Amoxicillin Amoxicillin Ampicillin Ampicillin Acts on both gram –positive & gram- negative bacteria Acts on both gram –positive & gram- negative bacteria Destroy by β-lactamase enzyme produced by certain bacteria Destroy by β-lactamase enzyme produced by certain bacteria

β-Lactamase inhibitors Such as : Such as : Clavulanic acid Clavulanic acid Sulbactam Sulbactam Tazobactam Tazobactam Themselves have no antibacterial activity. Themselves have no antibacterial activity. They inactivate β-lactamase enzyme They inactivate β-lactamase enzyme

β-Lactamase inhibitors (continue) Given in combination with β -lactamase sensitive antibiotics : Given in combination with β -lactamase sensitive antibiotics : Amoxicillin/clavulanic acid (augmentin ) Amoxicillin/clavulanic acid (augmentin ) Ampicillin/ sulbactam Ampicillin/ sulbactam

Therapeutic uses Upper respiratory tract infections Upper respiratory tract infections Lower respiratory tract infections Lower respiratory tract infections

Cephalosprins

Mechanism of action Inhibit bacterial cell wall synthesis Inhibit bacterial cell wall synthesis Bactericidal Bactericidal

Classification

1 st Generation Cephalosporins Cephalexin Cephalexin Given orally Given orally Effective against Gram positive bacteria & to some extent to Gram- negative Effective against Gram positive bacteria & to some extent to Gram- negative Effective in upper respiratory tract infections Effective in upper respiratory tract infections

2 nd Generation Cephalosporins Cefuroxime axetil (zinnat) Cefuroxime axetil (zinnat) Effective mainly on Gram –negative bacteria. Effective mainly on Gram –negative bacteria. Given orally Given orally

3 rd Generation Cephalosporins Ceftriaxone / Cefotaxime Ceftriaxone / Cefotaxime Not susceptible to hydrolysis by β- lactamase. Not susceptible to hydrolysis by β- lactamase. Effective against gram-negative bacteria Effective against gram-negative bacteria Given by intravenous route Given by intravenous route Effective in treatment of pneumonia caused by β-lactamase producing bacteria Effective in treatment of pneumonia caused by β-lactamase producing bacteria

Pharmacokinetics of cephalosporins Given parnterally or orally Relatively lipid insoluble Excreted Mostly unchanged in the urine. Half-life min (increased in renal failure)

Adverse effects of cephalosporins 1 Hypersensitivity reactions 2 Thrombophilibitis 3 Superinfections 4 Diarrhea

MacrolidesErythromycinAzithromycinClarithromycin

Mechanism of action Inhibit protein synthesis by binding to the 50 S subunit of the bacterial ribosomes Bacteriostatic Bactericidal at high concentration

Clarithromycin Stable to stomach acidity Stable to stomach acidity Inhibits cytochrome P-450 system Inhibits cytochrome P-450 system Metabolized in liver to active metabolite (antibacterial activity) Metabolized in liver to active metabolite (antibacterial activity) Half-life 6-8 hours Half-life 6-8 hours

Azithromycin Rapidly absorbed from GIT Food delays absorption Stable against gastric acidity Undergo some hepatic metabolism ( inactive ) Biliary route is the major route of elimination Only 10-15% excreted unchanged in the urine Half- life ( 3 days) Advantage over clarithromycin 1- Once daily dosing 2- No effect on cytochrome P- 450

Adverse effects

FluoroquinolonesMoxifloxacinCiprofloxacinGatifloxacin

Mechanism of action Inhibit DNA synthesis by inhibiting DNA Gyrase enzyme

CIPROFLOXACIN Antibacterial spectrum Mainly effective against G – bacteria ** Not effective against G+ and anaerobes

Pharmacokinetics Pharmacokinetics  Well absorbed orally ( available i.v )  Di & tri- valent cations interfere with its absorption  Concentrates in many tissues, esp. kidney, prostate, lung & bones/ joints  Poorly crossing BBB  Excreted mainly through the kidney  Half-life average 3 hrs

Gatifloxacin Is a new fluoroquinolones Is a new fluoroquinolones Has extended gram-positive activity Has extended gram-positive activity Given once daily Given once daily 1 st line treatment of LRTI 1 st line treatment of LRTI It is effective against community acquired It is effective against community acquired pneumonia pneumonia

Adverse effects of fluoroquinolones  N N N Nausea, vomiting & diarrhea CCCCNS effects – confusion, insomnia, headache, dizziness & anxiety. DDDDamage growing cartilage PPPPhototoxicity (avoid excessive sunlight )

Contraindications Adolescents ( under 18 years ) Adolescents ( under 18 years ) During pregnancy During pregnancy Breast feeding women Breast feeding women

Clinical Uses Acute exacerbation of chronic obstructive pulmonary disease Community acquired pneumonia Legionella pneumonia

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