Tetracyclines & chloramphenicol. Penicillin G, Amoxicillin,.ppt

pharmacology of tetracyclines and chloramphenicol

1. TETRACYCLINES

2. •Classification
•MOA
•AMS
•ADRs
•Uses

3. CLASSIFICATION
Group I :
•Tetracycline
•Oxytetracycline
•Chlorotetracycline
Group II:
•Methacycline
•Demeclocycline
•Lymecycline
Group III :
•Doxycycline
•Minocycline

4. MOA : Bacteriostatic
Bind with 30s ribosomal subunits
Interfere with attachment of
aminoacyl t-RNA to the mRNA –
ribosome complex
Inhibition of protein synthesis

5. AMS :Broad spectrum
•Now the spectrum is narrow
•Because of resistance
•N.gonorrhoeae,N.meningitidis
•Some Strepto, Staph, Enterococci
•G+ve bacilli : Clostridia,
Corynebacterium, Listeria,
Propionibacterium, B.anthracis

6. •G-ve bacilli :
H.ducreyi,Calym.granulomatis,V.ch
olerae,Y.pestis,Y.enterocolitica,
Campylobacter, H.pylori, Brucella,
P.multocida, F.tularensis, many
anaerobes
•Spirochetes
•Rickettsiae , Chlamydiae
•Mycoplasma & Actinomyces
•E.histolytica & Plasmodia

7. PHARMACOKINETICS
•Chelating property
•Form insoluble & unabsorble
complexes with calcium & other metals
•Milk, iron, nonsystemic. Antacids &
sucralfate decrease their absorption.
•Excretion by kidney ( through
Glomerular Filtration ).
•Doxycycline through bile into intestine
& then excreted through feces.

8. PREPARATIONS
1.Tetracycline:
Cap 250 , 500mg
Oint :3%
Drops : 1%
2.Doxycycline : cap/tab :100mg
3.Minocycline :cap 50,100mg

9. ADRs
1.Local:Nausea,
2.Vomitting,Diarrhoea,epigastric
distress,oesophagealulcerations
I.M injection causes pain ,
3.I.V injection causes thrombophlebitis
4.Liver damage :
•Fatty infiltration & jaundice
Phototoxicitycaused by:
. Demeclocycline& Doxycycline

10. 4.Teeth & bones
•Bind with calcium
•Calcium orthophosphate complex in
the teeth & bones
•Chelating property
•From midpregnancy to 5 months of
Extrauterine life –the deciduous teeth
are affected
•Between 3 months to 5 yrs of age
affect permanent anterior dentition
•Temporary suppression of growth

11. 5. Renal damage :
•Risk in preexisting renal disease
•Doxycycline safer
•Fanconi syndrome: It is caused by
outdated tetracyclines.
•Degraded products of outdated
tetracyclines damage proximal tubules.
e.g. Epitetracyclines,anhydrotetracyclines,
Exposure to acidic PH, moisture favour
such degradation

12. 6.Vestibular toxicity :
•Ataxia, Vertigo, nystagmus
•Common with minocycline
7.Antianabolic effects :
•↓ protein synthesis –catabolic
effect
•-ve nitrogen balance , ↑ blood
urea

13. 8.Diabetes insipidus: It is because
demeclocyclineantagonisesADH
action
9.Increases Intra Cranial Pressure:
10. Hypersensitivity:Skinrashes,
glossitis, pruritus ani, exfoliative
dermatitis,angioedema& anaphylaxis

14. 11.Superinfection :
•Common
•Marked suppression of the
resident flora in intestine, mouth,
skin or vagina

15. 1.THERAPEUTIC USES :
Sexually Transmitted Disease.s
a)LGV
b)GI
c)Non–specific urethritis
d)Syphilis
e)Gonorrhoea
f)Chancroid

16. 2.Chlamydial infection:
•Trachoma & Inclusion Conjunctavitis
•Ophthalmia neonatorum
•Psittacosis
3.Atypical pnuemonia
4.Cholera
5.Brucellosis

17. 6.Plague : highly effective
7.Relapsing fever
8.Rickettsial infections
9.Tetanus, anthrax,
actinomycosis
10.Listeria , tularaemia

18. 11.UTI
12.Amoebiasis
13.Chl. Resistant p. falciparum
malaria
14.Acne
15.COPD
16.Meningococcal meningitis –
prophylaxis -minocycline

19. Doxycycline: It is a semisynthetic agent.
It is highly potent because it can enter passively into the
cell of gram-negative bacteria as it is more lipid soluble
agent.
It is absorbed from g.i.t to the extent of 95-100%.
Presence of food in stomach does not interfere with its
absorption.92.3%.
Its metabolism is less & actively excreted through
feaces.
Its plasma t1/2 is 18-24 hours.

20. Its effect is least on alteration of intestinal flora and on
incidence of diarrhea is low .
Its phototoxic effect is high & its renal toxicity is low.
Uses of doxycycline:
1) Chlamydial non-specific urethritis/endocervicitis:
It is used in the dose of 100 mg b.d. orally for 7 days
2) Lymphogranuloma venereum:100 mg b.d.X 3 days.
3)Granulomainguinale/Donovanosis(Calymmatobacte-
rium granulomatis):100mg b.d. orally for 3 days

21. MCQ’S

22. 1.Tetracyclinesinhibit protein
synthesis by
(AI 2001, AIIMS Nov, 2005)
a)Inhibition of intiationand misreading
of m RNA
b)Binding to 30 S subunit and inhibiting
the binding of aminoacyl–t RNA to A
site
c)Inhibiting peptidyltransferase
activity
d)Inhibiting translocation

23. 2. The antibiotic that inhibits protein
synthesis by premature
termination and which structurally
resembles amino acylt-RNA is
(AIIMS Nov, 2002)
a)Tetracycline
b)Chloramphenicol
c)Puromycin
d)Erythromycin

24. 3. Treatment for Acne vulgarisis /are
(PGI Dec.2005)
a)Minocycline
b)Cis–retinoic acid
c)Etretinate
d)Rifampicin
e)Dapsone

25. 4. Photo toxicity is caused by all,
except
(DPG 2006)
a)Tetracycline
b)Atenolol
c)Griseofulvin
d)Aminodarone

26. 5. Which one of the folloeing
statement about doxycyclineis
false ?
a)It is bacteriostatic
b)It is excreted mainly in the feces
c)It is more active than tetracycline
against H pylori
d)It is used in Lyme’s disease

27. 6. The following tetracycline has
the protentialto cause
vestibular toxicity
a)Minocycline
b)Demeclocyline
c)Doxycycline
d)Tetracycline

28. 7. The most suitable tetracycline for
use in a patient with impaired renal
function is
a)Tetracycline
b)Demeclocycline
c)Oxytetracycline
d)Doxycyline

29. 8. Bactericidal inhibitiorsof protein
synthesis are
a)Tetracyclines
b)Aminoglycosides
c)Macrolides
d)Lincosamides

30. 9.The tetracylinewith highest
antileproticactivity is
a)Minocycline
b)Doxycycline
c)demeclocyclines
d)Oxytetracycline

31. CHLORAMPHENICOL

32. •MOA
•AMS
•ADRs
•Preparations
•Uses

33. MOA : Bacteriostatic
•Combines with 50s ribosomal subunits
•Interfere with the attachment of aminoacyl t-RNA to the ribosome m-
RNA complex
•Inhibition of protein synthesis

34. AMS: Broad spectrum
•Same as Tetracyclines except
some differences
•G+ve , G-ve, Rickettsiae,
Chlamydiae, mycoplasma

35. 1.It is highly active on Salmonella
2.More active on H. influenzae,
B.pertussis , Klebsiella,
Anaerobes,
3.Less active on G +ve cocci,
Spirochetes, certain
Enterobacteriaceae
4.Inactive on Entamoeba &
Plasmodia

36. ADRs
1.Bone Marrow Depression
•Aplastic A
•Thrombocytopenia
•Agranulocytosis
•Idiosyncratic reaction
•Dose & duration therapy
related

37. 2.Gray baby syndrome
It occurs at high dose ( > 100mg /kg) of
chloramphenicol.
•In neonates ( premature)
•Vomiting, hypotonia, hyperthermia
distention of abdomen., irregular
respiration, ashen gray cyanosis, stops
feeding, leads to cardiovascular collapse
& death
•Inability of the newborn to adequately
metabolize & excrete chloramphenicol

38. 3.Hypersensitivity:
•Rashes
•Fever
•Atrophic glossitis
•Angioedema
4.GIT : N,V,D
5.Local :
Pain, Thrombophlebitis
6.Superinfection

39. USES
1.Enteric fever
•Resistance
•0.5g q.i.d (10-14 days)
•Relapse : ~ 10 %
•Does not prevent / cure carrier
state

40. 2. H.influenzae miningitis
•50 -75 mg /kg /d x 2wks
•Excellent permeability in to CSF
3.Anaerobic infections:
•Wound infections
•Pelvic infections
•Brain abscess

41. 4.Intraocular infections
•Endophthalmitis
•Attains high conc. in ocular fluid
5.UTIs :
•If kidney is involved

42. PREPARATIONS
1.Capsule : 250, 500mg
2.Ointment :1% eye ointment
3.Drops : 0.5 %, 5% ear drops
Dose : 250 -500 q.i.d

43. MCQ’S

44. 1.A post operative patient developed septicemia
and was empirically started on combination
chemotherapy by a new resident doctor.
However, when the patient did not respond
even after 10 days of antibiotics treatment, the
review of the charts was done. It wasfoundthat
the resident doctor had started the combination
of antibiotics which was mutually antagonistic
in action . Which of the following is the most
likely combination that was given ? (AI 2004)
a)Vancomycinand amikacin
b)Cephalexinand gentamicin
c)Ampicillinand chloramphenicol
d)Ciprofloxacin and piperacillin

45. 2. Bone marrow aplasisis not seen
is not seen with (AIIMS May, 2007)
a)Chloramphenicol
b)Methicillin
c)Alpha methyl hydantoin
d)Chlopromazine

46. 3. Gray baby syndrome is casuedby
(DPG 2006)
a)Chlorpromazine
b)Chloramphenicol
c)Phenytoin
d)Gentamycin

47. 5. The most important mechanism by
which gram negative bacilli acquire
chloramphenicolresistance is
a)Decreasdpermeability into the
bacterial cell
b)Acquisition of a plasmid encoded for
chloramphenicolacetyl transferase
c)Lowered affinity of the bacterial
ribosome for chloramphenicol
d)Switching over from ribosomal to
mitochondrial protein synthesis

48. PENICILLIN-G (BENZYL PENICILLIN) :
Antibacterial spectrum: PnGis a narrow spectrum antibiotic; activity is limited
primarily to gram-positive bacteria, few gram negative ones and anaerobes
•Cocci: Streptococci (except viridans, group D or enterococci) are highly
sensitive, so are many pneumococci.
•Staph. aureus, though originally very sensitive, has acquired resistance to such
an extent that it must be counted out of PnGspectrum.
•Gram negative cocci—Neisseria gonorrhoeaeand N. meningitidisare
susceptible to PnG, though increasing number of gonococci have developed
partial and others high degree resistance.

49. Bacilli:
Gram-positive bacilli—majority of B. anthracis, Corynebacterium diphtheriae,
and practically all Clostridia (tetani and others), Listeria are highly sensitive,
so are spirochetes (Treponema pallidum, Leptospira, and others),
But Bacteroides fragilis is largely resistant.
Actinomyces israelii is only moderately sensitive
Majority of aerobic gram-negative bacilli, Mycobacterium tuberculosis,
rickettsiae, chlamydiae, protozoa, fungi and viruses are totally insensitive to
PnG.

50. Bacterial resistance : Many bacteria are inherently insensitive to PnG
because in them the target enzymes and PBPs are located deeper under lipoprotein
barrier where PnG is unable to penetrate or have low affinity for PnG
The primary mechanism of acquired resistance is production of penicillinase.
Penicillinase It is a narrow spectrum β-lactamase which opens the β-lactam ring and
inactivates PnG and some closely related congeners.
Majority of Staphylococci and some strains of gonococci, B. subtilis, E. coli, H.
influenzae and few other bacteria produce penicillinase.

51. The primary mechanism of acquired resistance is production of penicillinase.
Penicillinase : It is a narrow spectrum β-lactamase which opens the β-lactam ring and
inactivates PnG and some closely related congeners.
Majority of Staphylococci and some strains of gonococci, B. subtilis, E. coli,
H. influenzae and few other bacteria produce penicillinase.
The gram-positive penicillinase producers elaborate large quantities of the enzyme
which diffuses into the surroundings and can protect other inherently sensitive bacteria.
In gram-negative bacteria, penicillinase is found in small quantity, but is strategically
located in between the lipoprotein and peptidoglycan layers of the cell wall.

52. Staphylococcal penicillinase is inducible, and methicillin is an important inducer;
while in gram-negative organisms, it is mostly a constitutive enzyme.
Penicillinase has been successfully used to destroy PnG in patient’s blood
sample so that it does not interfere with bacterial growth when such blood is
cultured.
Some resistant bacteria become penicillin tolerant and not penicillin destroying.
Their target enzymes are altered to have low affinity for penicillin, e.g. highly
resistant pneumococci isolated in some areas have altered PBPs.

53. The methicillin-resistant Staph. aureus (MRSA) have acquired a PBP which
has very low affinity for β-lactam antibiotics.
Some penicillin resistant pneumococci and enterococci have altered PBPs.
The low level penicillin-resistant gonococci are less permeable to the drug,
while high degree resistant ones produce penicillinase, as do highly resistant
H. influenzae.
Both these appear to have acquired the penicillinase plasmid by conjugation
or transduction and then propagated it by selection

54. The gram-negative bacteria have ‘porin’ channels formed by specific proteins
located in their outer membrane.
Permeability of various β-lactam antibiotics through these channels differs:
ampicillin and other members which are active against gram-negative bacteria
cross the porin channels much better than PnG.
Some gram-negative bacteria become resistant by loss or by alteration of porin
cahannels.

55. Pharmacokinetics:
Penicillin G is acid labile, therefore destroyed by gastric acid.
As such, less than 1/3rd of an oral dose is absorbed in the active form. Absorption of
sod. PnG from i.m. site is rapid and complete; peak plasma level is attained in 30 min.
It is distributed mainly extracellularly; reaches most body fluids, but penetration in
serous cavities and CSF is poor.
However, in the presence of inflammation (sinovitis, meningitis, etc.) adequate
amounts may reach these sites.
About 60% is plasma protein bound. It is little metabolized because of rapid excretion.

56. The pharmacokinetics of PnG is dominated by very rapid renal excretion; about
10% by glomerular filtration and the rest by tubular secretion.
The plasma t½ of PnG in healthy adult is 30 min.
Neonates have slower tubular secretion—t½ of PnG is longer; but approaches
adult value at 3 months and then is even shorter during childhood.
Aged and those with renal failure excrete penicillin slowly.
Tubular secretion of PnG can be blocked by probenecid—higher and longer lasting
plasma concentrations are achieved.
Probenecid also decreases the volume of distribution of penicillins

57. Preparations and dose:
1. Sod. penicillin G (crystalline penicillin) injection 0.5–5 MU
i.m./i.v. 6–12 hourly.
It is available as dry powder in vials to be dissolved in sterile water at the time of
injection. BENZYL PENICILLIN 0.5, 1 MU injection.
Repository penicillin G injections:
These are insoluble salts of PnG which must be given by deep i.m. (never i.v.)
injection.
They release PnG slowly at the site of injection, which then meets the same fate
as soluble PnG.
1. Procaine penicillin G: inj. 0.5–1 MU i.m. 12–24 hourly as aqueous
suspension. Plasma concentrations attained are lower, but are sustained for 12–
24 hours; PROCAINE PENICILLIN-G 0.5, 1 MU dry powder in vial

58. Fortified procaine penicillin G inj: contains 3 lac U procaine penicillin and
1 lac U sod. penicillin G to provide rapid as well as sustained blood levels.
FORTIFIED P.P. INJ 3+1 lac U vial; BISTREPEN 6+4 lac U/vial
2. Benzathine penicillin G: 0.6–2.4 MU i.m. every 2–4 weeks as
aqueous suspension.
It releases penicillin extremely slowly—plasma concentrations are very low but
remain effective for prophylactic purposes for up to 4 weeks:
PENIDURE-LA (long acting), LONGACILLIN, PENCOM, 0.6, 1.2, 2.4 MU as dry
powder in vial

59. Adverse effects
Penicillin G is one of the most nontoxic antibiotics; up to 20 MU has been injected in
a day without any organ toxicity.
Local irritancy and direct toxicity Pain at i.m. injection site, nausea on oral ingestion
and thrombophlebitis of injected vein are dose related expression.
Toxicity to the brain may be manifested as mental confusion, muscular twitchings,
convul sions and coma, when very large doses (> 20 MU) are injected i.v.;
especially in patients with renal insufficiency.
Bleeding has also occurred with such high doses due to interference with platelet
function.
Intrathecal injection of PnG is no longer recommended because it has caused
arachnoiditis and degenerative changes in spinal cord

60. Accidental i.v. injection of procaine penicillin produces CNS stimulation, hallucinations
and convulsions due to procaine.
Being insoluble, it may also cause microembolis
Hypersensitivity:
These reactions are the major problem in the use of penicillins.An incidence of 1–10%
is reported.
Individuals with an allergic diathesis are more prone to develop penicillin reactions.
PnG is the most commondrug implicated in drug allergy, because of which it has
practically vanished from use in general practice.
Frequent manifestations of penicillin allergy are—rash, itching, urticaria and fever.

61. Wheezing, angioneurotic edema, serum sickness and exfoliative dermatitis are less
common.
Anaphylaxis is rare (1 to 4 per 10,000 patients), but may be fatal
All forms of natural and semisynthetic peni cillins can cause allergy, but it is more
com monly seen after parenteral than oral administration.
Incidence is highest with procaine peni cillin: procaine is itself allergenic.
The course of penicillin hypersensitivity is unpredictable, i.e. an individual who tolerated
penicillin earlier may show allergy on subsequent administration and vice versa.

62. There is partial cross sensitivity between different types of penicillins;
An individual who has exhibited immediate type of hypersensiti vity—urticaria,
angioedema, bronchospasm, anaphylaxis or serum sickness with one penicillin
should not be given any other type of penicillin.
However, if the earlier reaction had been only a rash, penicillin may be given
cautiously—often no untoward effect is seen.
History of penicillin allergy must be elicited before injecting it.
A scratch test or intradermal test (with 2–10 U) may be performed first

63. On occasions, this itself has caused fatal anaphylaxis. Testing with benzyl penicilloyl-
polylysine is safer.
However, a negative intradermal test does not rule out delayed hypersensitivity.
It should also be realised that presence of antibodies to penicillin does not mean
allergy to it, because practically everyone who receives penicillin develops
antibodies to it.
For the development of antibodies, penicillin or a product of it (mostly penicilloyl
moiety—major determinant) acts as a hapten.
There are many minor determinants as well. Topical application of penicillin is highly
sensitizing (contact dermatitis and other reactions).
Therefore, all topical preparations of penicillin (including eye ointment) have been
banned except for use of freshly prepared solution in gonococcal ophthalmia.

64. If a patient is allergic to penicillin, it is best to use an alternative antibiotic.
Hyposensitization by the injection of increasing amounts of penicillin intradermally
at hourly intervals may be tried only if there is no other choice
Superinfections These are rare with PnG because of its narrow spectrum; though
bowel, respiratory and cutaneous microflora does undergo changes.
Jarisch-Herxheimer reaction:
Penicillin injected in a syphilitic patient (particularly secondary syphilis) may
produce shivering, fever, myalgia, exacerbation of lesions, even vascular
collapse.
This is due to sudden release of spirochetal lytic products and lasts for 12–72
hours.
It does not recur and does not need interruption of therapy. Aspirin and sedation
afford relief of symptoms.