Concept of Azithromycin – This book covers the entire syllabus of “Pharmacology” prescribed by BNMC- for a diploma in nursing science & midwifery students. We tried to accommodate the latest information and topics. This book is an examination set up according to the teachers’ lectures and examination questions.
At the end of the book, previous questions are given. We hope in touch with the book students’ knowledge will be upgraded and flourish. The unique way of presentation may make your reading of the book a pleasurable experience.
Concept of Azithromycin
Properties
1. More acid-stabile
2. Rapid oral absorption
3. Marked tissue distribution and intracellular penetration.
4. Concentration in most tissues exceeds that in plasma.
5. High conc. attained inside macrophages and fibroblasts.
6. Volume of distribution is -30L/kg.
7. Slow release from intracellular sites contributes t½ of >50 hrs.
8. Largely excreted unchanged in bile, renal excretion is -10%
List the name of some contraindication of azithromycin.
Indications:
A. Respiratory tract infections
1. Pharyngitis
2. Tonsillitis
3. Sinusitis
4. Otitis media
5. Acute exacerbation of chronic bronchitis.
B. Skin and soft tissue infections
1. Uncomplicated genital chlamydial infections.
C. Prophylaxis and treatment of MAC in AIDS
D. Other potential uses in typhoid, toxoplasmosis & malaria.
Contraindications:
1. Hepatic impairment.
2. Side effects
3. Mild gastric upset
4. Abdominal pain
5. Headache
6. Dizziness
Resistance of azithromycin
Resistance
Resistance to macrolides is associated with:
- the inability of the organism to take up the antibiotic,
- the presence of efflux pumps,
- a decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of an adenine in the 235 bacterial ribosomal RNA in gram-positive organisms, and
- the presence of plasmidassociated erythromycin esterases in gram-negative organisms
such as Enterobacteriaceae. Resistance to erythromycin has been increasing, thereby limiting its clinical use (particularly for S. pneumoniae). Both clarithromycin and azithromycin share some cross- resistance with erythromycin, but telithromycin may be effective against macrolide resistant organisms.
Erythromycin
Properties:
- Bacteriostatic in action.
- Inhibit bacterial protein synthesis by binding with 50 S ribosome.
- Routes of administration: oral, parenteral.
- Distribution: widely distributed. cannot enter into brain
- Elimination: via the bile and faeces.
- Plasma half-life: 2 hours.
- First choice drug for diphtheria, whooping cough.
- Useful in penicillin allergic patients.
Indications of erythromycin
- An alternative to penicillin (as in allergy), such as streprococcal, pneumococcal, staphylococcal, treponemal and
- gonorrhoeal infection.
- An alternative to tetracycline in mycoplasma pneumoniae infection (in children).
- Diphtheria, whooping cough, camphylobacter enteritis and clostridial infections
Contraindication of erythromycin
- Hepatic.dysfunction
- Hypersensitivity to erythromycin.
Clarithromycin
- More acid-stable than erythromycin and is rapidly absorbed.
- Oral bioavailability is -50Vc due to first pass metabolism.
- Food delays but does not decrease absorption.
Indications
- Upper and lower respiratory tract infection.
✔ Sinusitis
✔ Pharyngitis
✔ Otitis media
✔ Whooping cough
- Atypical pneumonia
- Skin and soft tissue infections
- Eradication of Helicobacter pylori (triple drug regimen)
- MAC infection in AIDS.
Contraindications:
- Hypersensitivity to clarithromycin or anl, other macrolide antibiotics
Side effects (similar as erythromycin), also reported –
- Headache
- Taste disturbances
- Stomatitis
- Glossitis
- Cholestasis
- Jaundice
- Hepatitis
- Steven Johnson syndrome
Comparison between the macrolides
| Traits | Erythromycin | Clarithromycin | Azithromycin | Telithromycin |
| Oral absorption | Yes | Yes | Yes | Yes |
| Half-life (hours) | 2 | 3.5 | >40 | 10 |
| Conversion to an active metabolite | No | Yes | Yes | Yes |
| Percent excretion in urine | 1.5 | 50 | 12 | 13 |
Fluoroquinolones
Nalidixic acid is the predecessor to all fluoroquinolones, a class of man-made antibiotics. Over 10,000 fluoroquinolone analogs have been synthesized, including several with wide clinical applications. Fluoroquinolones in use today typically offer greater efficacy, a broader spectrum of antimicrobial activity, and a better safety profile than their predecessors.
Fluoroquinolones are –
- Ciprofloxacin
- Levofloxacin
- Moxifloxacin
- Gatifloxacin
- Sparfloxacin
- Ofloxacin
- Norfloxacin
- Lomefloxacin
Mechanism of action:
Quinolones
↓
Inhibit DNA gyrase (an enzyme that maintains the helical twist in DNA)
↓
Interfere with the supercoiling of DNA
↓
Inhibit replication and transcription
↓
Inhibit DNA synthesis
Indication and Adverse effects of quinolones
Indication:
1. Prophylaxis and treatment of urinary tract infection.
2. Bacillary dysentery(shigellosis)
3. Enteric fever (typhoid and paratyphoid)
4. Respiratory tract infection.
5. Gonorrhoea.
6. Septicaemia.
Adverse effects:
1. Hypersensitivity
2. Rash
3. Arthralgia
4. Photosensitivity
5. CNS disturbance
6. Dizziness
7. Headache
8. Confusion
9. Convulsions
10. GI tract
11. Nausea
12. Vomiting
13. Diarrhoea
14. Arthropathy
15. Children
16. Growing
17. adolescents
Ciprofloxacin
Ciprofloxacin [sip-row-FLOX-a-sin] is effective in the treatment of many systemic infections caused by gram-
Negative bacilli. Of the fluoroquinolones, it has the best activity against P. aeruginosa and is commonly used in cystic fibrosis patients for this indication. With 80% bioavailability, the intravenous and oral formulations are frequently interchanged.
Indications of ciprofloxacin:
1. Urinary tract infections.
2. Enteric fever (salmonellosis)
3. Gonorrhoea, Chancroid
4. Prostatitis.
5. Acute bacillary dysentery (shigellosis)
6. Bone and soft tissue infections (caused by streptococcus and gram negative organisms).
7. Respiratory infections.
8. Tuberculosis (as a combination chemotherapy)
9. Septicaemia (gram negative).
10. Conjunctivitis (by gram negarive bacreria)
Contraindications of ciprofloxacin:
➤ Pregnancy and Children.
➤ Known hypersensitivity to ciprofloxacin.
Adverse effects: Same as fluroquinolones
Resistance
Although plasmid-mediated resistance or resistance via enzymatic degradation is not of great concern, high levels of fluoroquinolone resistance have emerged in gram-positive and gram- negative bacteria, primarily due to chromosomal mutations. Cross-resistance exists among the quinolones. The mechanisms responsible for this resistance include the following:
1. Altered target: Chromosomal mutations in bacterial genes (for example, gyrA or parC) have been associated with a decreased affinity for fluoroquinolones at their site of action. Both topoisomerase IV and DNA gyrase may undergo mutations.
2. Decreased accumulation: Reduced intracellular concentration is linked to (1) porin channels and 2) efflux pumps. The former involves a decreased number of porin proteins in the outer membrane of the resistant cell, thereby impairing access of the drugs to the intracellular topoisomerases. The latter mechanism pumps drug out of the cell.
Sulfonamides
Sulfonamides were the first antimicrobial agents (AMAs) effective against pyogenic bacterial infections
Chemistry: All sulfonamides may be considered to be derivatives of sulfanilamide (p)) aminobenzene sulfonamide). Individual members differ in the nature of NI (Sulfonamido N) substitution, which governs solubility, potency and pharmacokinetic property. A free amino group in the para position (N4) is required for antibacterial activity.
Pharmacokinetics of sulfonamides:
➤ Route of administration: oral (well absorbed from upper GIT)
➤ Distribution: CSF, placenta (widely distributed) (20%-90% drugs protein bound)
➤ Metabolism: Liver (acetylation)
➤ Excretion: Kidney (tubular secretion & glomerular filtration)
Classification
➤Short acting (4-8 hr): Sulfadiazine
➤ Intermediate acting (8-12 hr): Sulfamethoxazole
➤ Long acting (~7 days): Sulfadoxine, Sulfamethopyrazine
➤ Special purpose sulfonamides: Sulfacetamide sod., Mafenide, Silver sulfadiazine, Sulfasalazine.
Anti-bacterial spectrum of sulfonamides
➤ Strep. pyrogens
➤ Strep. Pneumoniae
➤ H influenzae
➤ Nocardia
➤ Actinomyces
➤ Chlamydia trachomitis
Mechanism of action:
In many microorganisms, dihydrofolic acid is synthesized from p-aminobenzoic acid (PABA), pteridine, and glutamate (Figure). All the sulfonamides currently in clinical use are synthetic analogs of PABA. Because of their structural similarity to PABA, the sulfonamides compete with this substrate for the bacterial enzyme, dihydropteroate synthetase. They thus inhibit the synthesis of bacterial dihydrofolic acid and, thereby, the formation of its essential cofactor forms. The sulfa drugs, including cotrimoxazole, are bacteriostatic.
Indication of Sulfonamides
1. Typhoid (enteric fever) and paratyphoid fever.
2. Acute and chronic urinary tract infection (UTI)
3. Tropical application for infected burn (silver sulfadiazine)
4. Meningococcal meningitis (sulphadiazine)
5. Chloroquine resistance malaria (sulfadoxin)
6. Bacterial infection ofupper respiratory tract
7. Ulcerative colitis, inflammatory bowel disease.
8. Gut sterilization
9. Streptococcal infection, actinomycosis
10. Infection caused by H. inlluenza (otitis media).
11. Pharyngiris. toxoplasmosis
12. Bacillary dysentery
13. Trachoma & inclusion conjunctivitis
14. Uncomplicated gonorrhoea
15. Lymphogranuloma venereum and chancroid
16. Dermatitis and herpetiformis
Contraindication of Sulfonamides
1. Absolute contraindication:
➤ Pregnancy
➤ Premature infant
2. Use as last resorts:
➤ Renal impairment
➤ Dehydration
➤ History of hypersensitivity to sulfonamides
Adverse effect of Sulfonamides:
1. On Urinary system:
➤ Sulfonamides precipitates in acidic urine and form crystal which pass in urine. Renal irritation crystalluriaspasmodic pain (renal colic) haematuria → renal tubular necrosis oliguria → anuria
2. On Haemopoietic system:
➤ Bone marrow depression
➤ Aplastic anaemia
➤ Acute haemolytic anaemia
➤ Thrombocytopenia
➤ Eosinophilia
➤ Agranulocytosis
2. On gastrointestinal tract:
➤ Anorexia
➤ Nausea
➤ Vomiting
➤ Diarrhoea
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