Pharmacology PPT

1. Dr Chintan Doshi

3.  Sulfonamide: Sulfone + amide
Sulfanilamide [p-aminobenzene sulfonamide]

4. • Sulfadiazine
• Sulfisoxazole (Sulfafurazole)
Short acting
(4-8 hrs)
• Sulfamethoxazole
Intermediate acting
(8-12 hrs)
• Sulfadoxine
• Sulfamethopyrazine
Long acting
(7-8 days)
• Sulfacetamide sodium, Mafenide
• Silver sulfadiazine, Sulfasalazine
Special purpose
sulfonamides

5. Dihydropteroic acid synthetase
Glutamate
Dihydrofolate reductase
Sulfonamide
Trimethoprim
=
=

6.  Bacteriostatic action evidence by:
• PABA antagonizes action of sulfonamides
• Only those microbes which synthesize their own folic
acid are susceptible to sulfonamide
 Human cells directly absorb preformed folic acid,
supplied in diet & not affected by sulfonamides.

7.  Microorganisms that susceptible to sulfonamide:
 Staph. aureus, gonococci, meningococci, E. coli,
Shigella respond, but majority are resistant.
 Anaerobic bacteria not inhibited
Streptococcus pneumoniae
Streptococcus pyogenes
Haemophilus influenzae
Nocardia
Actinomyces
Chlamydia trachomatis

8. • Rapidly absorbed in GIT, reach maximum concentration
within 4-6 hrs
• Widely distributed in body – cross placenta & Blood
brain barrier
• Metabolized in liver by acetylation
• Excreted by kidney through glomerular filtration
(metabolites insoluble in acidic urine - crystalluria)

9. • High plasma protein binding & slow excretion
• Ultra long acting agents (half life → 7-9 days)
• Not suitable for acute pyogenic infection
• Use: in combination with pyrimethamine for treatment of
:malaria
: Pneumocystis jiroveci pneumonia in AIDS patients
: Toxoplasmosis
Sulfadoxine Sulfamethopyrazine

10. • Highly soluble
• Only mild irritating to eye in concentration up to 30%
• Topical - high concentration in anterior segment & aqueous
humour
• Use: ocular infection due to susceptible bacteria & chlamydia
: ophthalmia neonatorum by Ch. oculogenitalis
• S/E: Sensitivity reaction (incidence low but when occur stop drug)
Sulfacetamide sodium

11. • Topically (1% cream)
• Inhibit gram –ve & gram +ve bacteria, against pseudomonas, clostridia
• Active in presence of pus
• Use: burn dressing to prevent infection (not treat already infected case)
• S/E: burning sensation & severe pain on raw surface
: acidosis & hyperventilation
: allergic reaction
• Active against bacteria & fungi, even though resist to other
sulfonamide like pseudomonas
• Slowly release silver ions
• Use: prevent infection of burn surface & chronic ulcers(1% cream)
• S/E: burning sensation & itch
Mafenide
Silver sulfadiazine

12. • Degraded by bacterial flora of colon
Sulfasalazine
5-ASA Sulfapyridine
(5-aminosalicylic acid) ↓
↓ carrier for 5-ASA
antiinflammatory
 USE: Ulcerative colitis & Rheumatoid arthritis
 Dose: 3-4 gm/day (oral)
Sulfasalazine

13. • nausea, vomiting, epigastric pain
• jaundice, hepatic dysfunction, necrosis of liver
• Acetylated metabolites less soluble in acidic urine &
get precipitated in kidney
• Minimized by→ adequate intake of water
→ alkalization of urine(↑ excretion)
GI side effects
Crystalluria & Renal toxicity

14. • 2-5% & after a week of
therapy
• rash, urticaria, drug fever,
Photosensitization
• Serious reaction like
stevens jhonson
syndrome, exfoliative
dermatitis (with long
acting agents)
Hypersensitivity reactions

15. displace bilirubin from protein binding site
↓
free bilirubin pass through BBB
↓
deposited in basal ganglia & subthalamic nuclei
↓
kernicterus (encephalopathy)
 Avoid in neonates & pregnancy
• Acute haemolytic anaemia:
Rare but develop in G6PD deficient patients
• Agranulocytosis & aplastic anaemia extremely rare
Effect on haematopoietic system
Kernicterus in neonates

16. 1) Cotrimoxazole
2) Cotrimazine
3) Sulfadoxine + Pyrimethamine

17. Fixed Dose Combination
Cotrimoxazole
Sulfamethoxazole + Trimethoprim

18. • Diaminopyrimidine related to pyrimethamine
• Selectively inhibit DHFRase (dihydrofolate reductase)
• >1,00,000 times more active against bacterial DHFRase

19. • Same half life (10 hrs)
• Optimal synergy at concentration ratio :
sulfamethoxazole 20 : Trimethoprim 1
• Trimethoprim enters many tissue, ratio obtained in plasma
↓
• Trimethoprim → cross placenta & BBB
→ rapidly absorbed
• Trimethoprim 40% plasma protein bound while Sulfamethoxazole
65% bound
dose ratio 5:1

20.  Additional organism:
 Sulfonamide resistant strain:
 Not against: Pseudomonas, B. fragilis, enterococci
Salmonella typhi
Serratia
Klebsiella
Yersinia enterocolitica
Pneumocystis jiroveci
Staphylococcus aureus
Streptococcus pyogenes
Haemophilus influenzae
E. Coli
Gonococci
meningococci

21. • Sequential blockade, supra additive effect

22. • Individually bacteriostatic, but combination
bacteriocidal
• Reduced development of resistance
• Wide spectrum
• Safe & well tolerated
• Cost effective

23. Trimethoprim (mg) Sulfamethoxazole (mg)
Tablet 80 400
Double strength 160 800
Pediatric tablet 20 100
IV injection/5 ml 80 400

24. Urinary tract infections:
• Acute & uncomplicated cases respond rapidly
• DS tablets BD for 5-10 days
• Acute cystitis – 4 tab of DS formulation (single dose)
Prostitis:
• Acute – one DS tab daily for 3 weeks
• Chronic: 6-12 weeks
 Nocardiosis:
• Drug of choice for pulmonary lesion & abscess

25. Respiratory tract infections:
• Bronchitis, facio maxillary infections, otitis media by
Pneumococcus & H. influenza
• Dose: One DS tab BD
Sexually transmitted diseases:
• 3rd choice drug for Chancroid- 1 DS tab BD for 7-10 days
• also used for Urethritis, lymphogranuloma, gonorrhoea
Pneumonia:
• Pneumocystis jiroveci – in neutropenic & AIDS patient

27. Bacterial diarrhoea & Dysentery:
• Acute gastroenteritis by Shigella & Yersinia enterocolitica,
Traveler’s diarrhoea due to E. coli & Cholera by V. cholera
• Alternative to fluoroquinolones
As alternative drug:
• Typhoid – 1 DS tab BD for 2 weeks
 Intravenous cotrimoxazole – severe infection
 Dose: 80mg Trimethoprim + 400mg sulfamethoxazole
↓
diluted in 125 ml of 5% dextrose(i.v. infusion over 60-90min)

28. • Nausea, vomiting, stomatitis, headache
• Fever, rash, bone marrow hypoplasia (up to 50%)
• Megaloblastic anaemia
• Uremia
• Bone marrow toxicity – elderly
• Blood dyscrasias – rarely

30. • Synthetic AMA having quinolone structure
• Against gram –ve bacteria
• New flourinated compound → (-) gram +ve bacteria
• Mid 1960 – Nalidixic acid
- limited use UTI & GIT infection
• Early 1980 – Fluoroquinolones
• fluorination of quinolone structure at position of 6 and
introduction of piperazine substitution at position 7

31. Nalidixic acid
 Active against:
• Gram –ve bacteria – E.coli, Proteus, Klebsiella, Shigella,
but not Pseudomonas
 Mechanism of action:
• Bactericidal
• Inhibit DNA gyrase
Pharmacokinetic:
• Absorbed orally
• High plasma protein binding & metabolized in liver
• Plasma half life 8 hrs
• Excreted in urine

32.  Adverse effects:
• GI upset & rashes
• Neurological toxicity – headache, drowsiness, vertigo, visual
disturbance, seizure
• Phototoxicity rare
• Haemolysis in G6 PD deficient pt
 Uses:
• As urinary antiseptic
• Diarrhoea
 Dose:
• 0.5-1 gm TDS or QID

34. 1st generation
fluoroquinolones
• Norfloxacin
• Ciprofloxacin
• Ofloxacin
• Pefloxacin
2nd generation
fluoroquinolones
• Levofloxacin
• Lomefloxacin
• Sparfloxacin
• Moxifloxacin
• Gemifloxacin
• Prulifloxacin
• Trovafloxacin
• Alatrofloxacin
• Fleroxacin
1st generation : one flourine substitution
2nd generation: additional fluorine & other substitution
: extended activity to gram +ve cocci & anaerobes
: metabolic stability (long half life)

36.  There is necessary to prevent excessive positive super coiling of
DNA strand, when they separate for replication or transcription
DNA gyrase: in gram –ve bacteria
 FQs bind to A subunit with high affinity interfere with
its function
A subunit – nicking of DNA
B subunit – introduces negative supercoiling
A subunit – reseals the strands

38.  Topoisomerase IV: in gram +ve bacteria
• Nicks & separates daughter DNA strands
• FQs targets Topoisomearse IV with greater affinity & confer
potency against gram +ve bacteria
 Bactericidal action – digestion of DNA by exonuclease
 mammalian cells – topoisomerase II (remove +ve supercoiling)
• Low affinity for FQs → low toxicity to host cells

39. • Salmonella, Pseudomonas, Staphylococci, Gonococci, Pneumococci

40. • Bactericidal activity & high potency
• Long post antibiotic effect
• Low frequency of mutational resistance
• Low propensity to select plasmid type resistant mutant
• Protective intestinal streptococci & anaerobes are spared
• Active against many beta lactam & aminoglycoside resistant
bacteria
• Less active at acidic pH

41. Ciprofloxacin
• Prototype drug
• Most potent 1st generation FQ
• Aerobic gram –ve bacilli
 gram +ve bacteria inhibited at high concentration
 Resistant ones: Bacteroides fragilis, Clostridia,
anaerobic cocci
E. Coli
Klebseila
Salmonella typhi
Shigella
Proteus
N. Gonorrhoea
N. Meningitidis
H. influenzae
Campylobacter jejuni
V. cholerae

42. Pharmacokinetics:
• Rapidly absorbed orally, food delays absorption
• First pass metabolism
• Good tissue penetration- lung, sputum, muscle, prostate, phagocytes,
but low in CSF, bone & aqueous
• Excreted in urine except pefloxacin & moxifloxacin
Adverse effects: (10%)
o GIT: nausea, vomiting, bad taste, anorexia (diarrhoea infrequent)
o CNS: dizziness, headache, restlessness, anxiety, insomnia, impairment
of concentration (caution during driving)
o Skin: rash, pruritus, photosensitivity, urticaria, swelling of lips
o Tendinitis & tendon rupture: higher in those above 60 yr & receiving
steroids

43. Contraindication:
• Pregnancy & children
Interactions:
• ↑concentration of theophylline, caffeine, warfarin
by inhibiting metabolism
• NSAIDs enhance CNS toxicity of FQs
• Antacid, sucralfate, iron salt - ↓absorption of FQs

44. Uses:
 Urinary tract infections:
• High cure rates, even in complicated cases or those with
indwelling catheters/prostitis
• High success rates than cotrimoxazole
 Gonorrhoea:
• Single 500mg dose – 100% curative in non PPNG & PPNG
• Resistance – not 1st line drug
 Chancroid:
• Second line drug – 500mg BD for 3 days
• Alternative to ceftriaxone/ azithromycin

45.  Bacterial gastroenteritis:
• Currently most commonly used
• Reserved for sever cases due to E.choli, Shigella, Salmonella,
Camp. jejuni infection
• ↓ stool volume in cholera
 Bone, soft tissue & wound inection:
• Osteomyelitis & joint pain – prolong treatment with high dose
(750 mg BD for 6-8 weeks)
• Diabetic foot – with clindamycin / metronidazole (cover anaerobes)
 Tuberculosis:
• Second line drug against mutidrug resistant TB

46.  Typhoid:
• First choice of drug
• India – 95% S. typhi were sensitive
• Dose: 750 mg BD for 10 days
: unable to take orally – 200 mg i.v. 12 hrly
: 750 mg BD for 4-8 weeks for carriers
• Advantages: quick defervescene
: early abetment of symptoms
: prevention of carrier state
 Gram –ve septicemia:
• Parenteral ciprofloxacin combined with 3rd generation
cephalosporin or aminoglycoside

47.  Respiratory tract infections:
• Treat Mycoplasma, Legionella, H. influenza infection
• Low susceptibility for pneumococci, streptococci
• 2nd generation FQs – pneumonia & bronchitis
• US FDA approved for inhalational anthrax
 Meningitis:
• Gram –ve bacterial meningitis, specially in
immunocompromised patients or CSF shunt
 Prophylaxis:
• Infection in neutropenic / cancer patients
 Conjuctivitis:
• By gram –ve bacteria , topical therapy

48. Norfloxacin
• Less potent
• Gram +ve & pseudomonas not inhibited
• Low penetration in tissue – non therapeutic level
• Use: urinary & genital infections, bacterial diarrhoea
• Not use for respiratory or other systemic infection
• Dose: 400 mg BD
• methyl derivative of norfloxacin
• More lipid soluble & better penetration in tissue (also in CSF)
• Longer half life – cumulates on repeated dosing
• Use: preferred for meningitis & systemic infection
• Dose: oral - 400 mg BD; i.v. 400 mg
• Dose reduced in liver disease
Pefloxacin

49. Ofloxacin
• Less active against gram –ve bacteria
• Good activity against - gram +ve, anaerobes, chlamydia,
mycoplasma
• More lipid soluble
• Use: mutidrug resistant TB, multidrug therapy for leprosy
: chronic bronchitis & respi. infection, ENT infection
: gonorrhoea, urethritis
• Dose: oral - 200-400 mg BD; i.v. 200 mg

50. Levofloxacin
• Levo isomer of ofloxacin
• Strep. pneumococci & other Gram +ve, gram –ve & anaerobes
• Oral bioavailability 100%
• Single daily dose sufficient – slow elimination
• Theophylline, warfarin, cyclosporine, zidovudine P/K unchanged
during levofloxacin treatment
• Use: community acquired pneumonia
: exacerbation of chronic bronchitis
:sinusitis, pyelonephritis, prostitis, UTI, skin/soft tissue infection
• Dose: oral - 500mg OD, i.v. 500 mg/100ml inj

51. Lomefloxacin
• More active against some gram –ve bacteria, chlamydia
• Long half life – single daily dose
• S/E: phototoxicity, Q-T prolongation
• Dose: 400 mg OD
• Gram +ve, B. fragilis, anaerobes, mycobacteria
• Use: pneumonia
: exacerbation of chronic bronchitis
: sinusitis & other ENT infections
• S/E : phototoxicity, Q-T prolongation
• Dose: 200-400mg OD
 Both Withdrawn in USA available in india
Sparfloxacin

52. • High affinity for bacterial topoisomerase IV
• Used for gram +ve coccal (ENT & respiratory) infections
• S/E: QT prolongation, arrhythmia, phototoxicity,
unpredictable hypoglycemia
• Banned in India March 2011
• Long acting agent
• Gram +ve, beta lactam resistant, anaerobes
• Most potent FQs against M. tuberculosis
• Use: pneumonia, bronchitis, sinusitis, otitis media(not in UTI)
• not give to – predisposed to seizure, receiving pro arrhythmic
drugs; liver disease pt
• Dose: 400 mg OD
Gatifloxacin
Moxifloxacin

53. • Long acting agent
• Gram +ve, beta lactam resistant, anaerobes
• Use: life threatening infections
• S/E: hepatotoxicity
• Dose: 200 mg orally/i.v. OD
• Withdraw from European countries & USA
• Prodrug for Trovafloxacin
Trovafloxacin
Alatrofloxacin

54. • aerobic gram +ve, some anaerobes
• excreted in urine – dose need to be halved
if Cr clearance<40 ml/min
• Use: community acquired pneumonia, chronic bronchitis
• S/E: nausea, diarrhoea, headache, dizziness, skin rashes
: ↑ serum amino transferase & warfarin effect
: QT prolongation
• Dose: 320 mg OD for 5-7 days
Gemifloxacin

55. • Prodrug of ulifloxacin
• Both gram +ve & gram –ve bacteria
• Use: acute exacerbation of chronic bronchitis
: uncomplicated/complicated UTI
• S/E: same as ciprofloxacin, but NO QT prolongation
• Dose: 600mg OD single dose uncomplicated UTI
: up to 10 days for complicated UTI & bronchitis
Prulifloxacin

56. • Broad spectrum(gram –ve & gram +ve methicilin sensitive strain)
• Long acting agent
• Use: UTI, gonorrhoea, respi infection, skin & soft tissue infection,
enteritis
• S/E: GIT, CNS, skin
• Dose: 400 mg OD
Fleroxacin

57. • Under going phase III
• Activity markedly increases at acidic pH
• Very high safety profile
• Widest spectrum
• Long half life
• Clinical option for its trial – UTI, community acquired pneumonia,
bronchitis, COPD, intra abdominal & skin infection
Finafloxacin

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