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1- Narrow spectrum: Penicilline G , Erythromycin , Streptomycin , Sulphonamides
2- Wide spectrum: Chloramphenicol , Tetracycline
Cell wall
Cell membrane
Ribosoms
DNA Chromosome
d-alanine + d-alanine
Cycloserine
Di-d-alanine
N-acetyl
muramic a.
Peptidoglycan
Vancomycin,
Teicloplanin &
Bacitracin
Elongation
Lactam-Cross linking to form
stable cell wall
-
-
-
PABA+ PteridineSulpha Dihydropteroate synthase
Folic a.
Trimethoprim &
PyrimethaminereductaseefolatDihydro
DHF acid
Anti-viral & cancer
GriseofulvinMetronidazole
Chloro uine
THF acid (Foloinic a.)
Purines
DNA
Quinolones
Rifampicin
gyraseDNA
Super-coiled DNA
m-RNA
polymeraseRNA
-
-
-
-
-
Fosfomycin -
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1-Inhibitors of cell wall synthesis
-Lactam Antibiotics(Penicillins, Cephalosporins, Monobactams & Carbapenems )
1-PENICILLINS
- They are erivatives of 6-Aminopenicillanic acid
(containing -lactam ring)
- Obtained naturally from penicillinium molds & synthetically.
*Preparations of Penicillins :1-Benzyl Penicillin (Penicillin G) : Natural Penicillin has the following side effects:
a- Short duration of action (6 Hours) .
b- Acid sensitive (Destroyed by gastric acidity) Not effective orally.
c- -Lactamase (Penicillinase ) sensitive (Not effective in -lactamase
secreting organisms).d- Narrow spectrum (Not effective against Gram-ve Bacilli )
2- Long Acting Penicillins :1-Procaine penicillin G & Fortified Procaine Penicillin G
2- Benzathine Penicilline G
3- Acid Resistant Penicillins : Orally
- Phenoxymethyl penicillin (Penicillin V)
4- - Lactamase (Penicillinase) Resistant:- Methicillin:
• Some strains of Staph-Aureus become resistant
(MRSA infection)
•••• Not used due to its nephrotoxicity
5- Acid & -Lactamase Resistant Penicillins :
-Effective orally in treatment of Staph . Infections.1- Oxacillin 2- Cloxacillin 3- Dicloxacillin 4- Flucloxacillin
5- Nafcillin Entero-Hepatic Circulation.
6-Broad-Spectrum Penicillins :
- Effective against Gram + ve & -ve organisms but not effective against:Pseudomonas aerugenosa , Proteus & Klebsiella
- -Lactamase sensitive but Acid resistant (effective orally)
- They include: Ampicillin – Proampicillin –Amoxycillin.
1- Ampicillin: Incompletely absorbed orally & affected by food.
2- Pro-Ampicllins (Esters of Ampicillin):- As (Pivampicillin. - Bacampicnllin . - Talampicillin. - Epicillin ).
- Prodrugs, de-esterified in gut mucosa and liver Release Ampicillin[No effect on intestinal flora.]
3- Amoxycillin Similar to Ampicillin but:
a- Better oral absorption& not affected by food
b- Longer duration of action.
c- Less effective againest Shigella & Salmonella .
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7- Extended Spectrum (Antipseudomonal) Penicillins:
- Broad spectrum + Effective against Pseudomonas, Proteus & Klebsiella
- They are -Lactamase sensitive.
1-Carboxypenicillins 1-Carbenicillin IM & IV
2-Carbenicillin indanyl Orally
2-Ureidopenicillins 1-Ticracillin IM & IV2-Piperacillin IV
3-Azlocillin IV
4-Mezlocillin IV
Pharmacokinetics of Penicillins :
1- After absorption, they are distributed All over the body:
- Very little passage across normal BBB. Pass easily inflamed meninges.
- Pass easily placental barrier; but not Teratogenic
2- They are bound to plasma proteins
3- Active renal tubular excretion , inhibited by Probenecid.Nafcillin is excreted mainly in bileEnterohepatic circulation
Mechanism of action of Pencillins :
1- Bactericidal Antibiotics.
2-They bind to specific Penicillin – Binding –Protein (PBP):
a- transpeptidase enzyme responsible for cross – linking of peptidoglycans ,a final step in cell wall synthesis Cell Wall Synthesis .
b- Activate autolytic enzymes (Autolysins) Lysis of cell wall.
Spectrum: A-Narrow Spectrum Penicillins :
- Gram +ve Cocc: Staphylococci, Streptococci, Enterococci & Pneumococci
- Gram -ve Cocci: Gonococci & Meningococci.
- Gram +ve Bacilli: C lostridia: tetani (Tetanus) & perfringens (Gas gangrene) -
C orynebacterium diphtheriae (Diphtheria), Anthrax bacillus
(Anthrax)& Listeria monocytogenes (Listeriosis)
- Actinomyces: (Actinomycosis).
- Spirochetes: Treponema pallidum (Syphilis).
B-Broad Spectrum Penicillins- As narrow spectrum + Gram-ve.Bacilli: Salmonella , Shigella, Escherichia
coli, H aemophilus influenza & H elicobacter pylori.
C-Extendgd Spectrum (Antipseudomonal) Penicillins:
- As broad spectrum + Pseudomonas aerugenosa, Proteus & K lebsieilla
pneumonia.
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Uses of Penicillins :
a-Treatment of : ……. (see spectrum)…………..
b- Propnylaxis of : 1- Streptococcal infection in Rheumatic fever: Benzathine penicillin 1.2
million U IM / month, for 5 years or up to age of 20 which is ever longer.2- Subacute bacterial endocarditis: Procain penicillin before operations
3- Gonorrheal neonatal ophthalmia: Benzyl penicillin eye drops
Adverse Effects Of Penicillins :
1- Allergic Reactions: Urticaria ,angioedema &Anaphylactic shock
a- Caused by degradation products esp. penicilloic acidb- Avoid by : -Ask for previous history . –Dermal sensitivity test .
c- Never reuse penicillin again .d- Cross allergy with other B-lactam antibiotics.
e- Ampicillin induces skin rash in 10% of patients & in all patients withinfective mononucleosis & taking allopurinol
2- Jarisch-Herxheimer reactions :a- Febrile reaction accompanied with exacerbation of local syphilis on 1
st
injection in ttt of Syphilis due to libration of toxins
b- Continue penicillin therapy.3- Diarrhea due to superinfection , specially after oral Ampicillin :
a- Candida albicans: Treated by Nystatin.b- Antibiotic associated (Pseudomembraneous) colitis:
Treated by: Oral Vancomycin or Metronidazole.
4 - CNS irritation (seizures) may occur if large dose or intrathecal injection of
penicillin.5- Na+
or K+
overload, which could be dangerous in patients with renal or cardiac
problems,as we use Na+
or K+
salts of Penicillins.
6-Acute Interstetial Nephritis with Methicillin
7- Platelet dysfunction with Carbinicillin – Ticracillin
*NB: -Lactamase (Penicillinase) Inhibitors ;
1- Examples: Clavulanic acid, Sulbactam & Tazobactam
2- They have no or insignificant antibacterial activity
3- They protect penicillins from inactivation & degradation by -lactamases secreted
by some bacteria e.g. Staph aureus4- Preparations : a- Clavulanic acid + Amoxicillin “Augmentine”
b- Clavulanic + Ticarciilin
c- Sulbactam + Ampicillin “Unasyn”
d- Tazobactam + Piperacillin " Tazocin"
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2- CEPHALOSPORINS
1- -Lactam antibiotics & Anti- bacterial activity is similar to penicillin but more resistant
to -Lactamase
2- Mechanism of action: as penicillin , Bactericidal & cell wall synthesis.
3- All cephalosporins are not active against MRSA, Enterococci, C. difficile & Listeriamonocytogenes
Classification:
1st Generations 2nd Generation 3rd Generation 4th Generation
Spectrum:Broad spectrum.Active mainly
against gram + veorganisms
Broad spectrum.Similar to 1
st
generation but less active on Gram +ve &
more on Gram –ve
Broad spectrum similarto 2
ndgeneration but
less on Gram +ve &
more on Gram -ve.
Similar to 3rd
generation but
more resistant to
-lactamase
enzyme.Passage across BBB:
Do not cross BBB
NOT effective in
meningitis
Do not pass BBB
except Cefuroxime.
Passes BBB useful
in meningitisPasses BBB
useful in
meningitis
Preparations:Oral:CephalexinCephadroxil
Cephradin (Velosef)
Parenteral : Cephapirin
Cephazoline
Cephradin (Velosef)
Oral :
Cefaclor (Bacticlor)
Cefprozil (Cefzil) Cefuroxime (Zinnat)
Loracrbef (lorabid)
Parenteral : Cefuroxime (Zinnat )
Cefamandole
Cefoxitin
Oral :
Cefixime
Cefpodoxime
Parenteral:
Cefotaxime (Claforan)
Ceftriaxone(Rocephin)
Cefoperazone(Cefobid)
Ceftazidime (Fortum)
Moxalactam
Parenteral: Cefe pime -
Cef pirome
NB: - Fate of Cephalosporins depends on Active renal tubular excretion which is by
Probenecid (Similar to Penicillins)
- Cefoperazone & Ceftriaxone excreted in bile & faeces
Therapeutic Uses of Cephalosporins :
1- Infections resistant to Penicillin e.g. staphylococci & gonorrhea (Ceftriaxone is the
drug of choice).
2- Anaerobic infection
3- Respiratory tract infection
4- Urinary tract infections specially Gram -ve.5- Meningitis: Cefuroxime, Cefotaxime & Ceftriaxone
6- Typhoid fever: (Ceftriaxone & Cefperazone).
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Side effects &Toxicity:
1- Allergy & Cross-allergy with penicillins (10%).
2- Bleeding disorder: due to:
- Platelet dysfunction caused by Moxalactam
- Hypoprothrombinemia caused by Cefamandole & Cefperazone
(can beprevented by Vit K)
3- Diarrhea, GIT upsets and Superinfections……………..
4- Disulfiram like reaction
5- Irritant: - IM Painful
- IV Thrombophlebitis.
6- Nephrotoxicity specially Cephaloridine . It is increased by concurrent use of Loop
diuretics & Gentamicin & NSAID.
3- Monobactams:
1- Example: Aztreonam (Azactam)2- 100% bioavailabity after IM. Depends on renal excretion.
3- It is -Lactamase resistant & Narrow spectrum (Affects mainly Gram -ve bacteria
including P. aeruginosa & not effective against Gram + ve or anaerobes.)
5- Side Effects:
- Superinfection with Staph.
- Skin rash & Phlebitis
4- Carbapenems (Imipenem, Meropenem & Ertapenem) 1- Imipenem
1- Wide spectrum: Gram +ve, Gram -ve and anaerobes. Used IV in serious mixed
aerobic & anerobic infections..2- Inactivated by renal tubular dipeptidase enzyme Nephrotoxic metabolite.
o So, it is not given alone, but in combination with Cilastatin, which is adipeptidase enzyme inhibitor (Imipenem + Cilastatin = Tienam)
3- Side effects:- Allergy and cross-allergy with other -Lactams .
- GIT disturbances.
- Seizures.
---------------------------------------------------------------------------------------------------------------
2- Meropenem :- Similar to lmipenem but not metabolized by dipeptidase enzyme
- Less side effects & less liable to produce seizures
---------------------------------------------------------------------------------------------------------------
3- Ertapenem:- Similar to Meropenem, but has longer half life, so, given parenteraly once daily
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NB:Other inhibitors of cell wall synthesis
1-Vancomycin (Vancocin) - Kinetics: Not absorbed orally. Used by slow IV Infusion (over 30 min. – 1 hr).
Passes BBB in Meningitis. Excreted in urine by glomerular filtration.
- Mechanism: Bactericidal Inhibits Cell wall synthesis- Spectrum: Affect Gram +ve organisms including MRSA, Enterococci, C. difficile, & L.
monocytogenes &
-Uses:a- Orally: in pseudomembranous colitis caused by C. difficile
b- IV : - ttt of Penicillin-Resistant Staph(MRSA), Strept & Enterococcal infections
- Prophylactic before dental operations in patients with prosthetic valves.
- Side effects:a- Ototoxic
b- Nephrotoxicc- Rapid infusionHistamine release "Red man syndrome".
---------------------------------------------------------------------------------------------------------------2- Teicloplanin
As vancomycin but given once daily IM or IV
---------------------------------------------------------------------------------------------------------------
3-Bacitracin 1- Bactericidal, Cell wall synthesis
2- Spectrum: Gram +ve organisms, Used Topically in Staph aureus infections.
3- Side effects: Nephrotoxic if used systemically---------------------------------------------------------------------------------------------------------------
4- Fosfomycin- Bactericidal, formation of N-acetyl muramic acid present in bacterial cell wall
- Spectrum: Gram +ve & -ve organisms
- Used as single oral 3-gm dose in non-complicated urinary tract infection in women
---------------------------------------------------------------------------------------------------------------
5-Cycloserine- Used as 2
ndline Anti-TB agent - SE.: Seizures & Psychosis
2-Inhibitors of cytoplasmic membrane
Polymixin B &E.1- Cytoplasmic membrane function leakage of cell contents bactericidal
2- Affects mainly Gram -ve organisms esp. pseudomonus3- Not absorbed orally & nephrotoxic , so used ONLY locally
DaptomycinIt affects cell membrane permeability. Used IV in vancomycin resistant infections (VRSA).
Not used in pneumonia as it is inhibited by surfactant.
NB: Polypeptide antibiotics:- Bacitracin (effective against Gram +ve) - Polymixins (effective against Gram -ve)
They are bactericidal & highly nephrotoxic, so, used locally only
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3-Inhibitors of proteine synthesis
1-Macrolide Antibiotics(Erythromycin – Clarithromycin – Azithromycin – Roxithromycin – Spiramycin)
1- Eryhtromycin
Pharmacokinetics:
1- Absorbed orally, but acid-sensitive, so used as enteric coated or as an esteolate ester .
2- Distributed all over the body except CSF
3- Metabolized in liver
4- Excreted in bile Enterohepatic circulation.
---------------------------------------------------------------------------------------------------------------
Mechanism of action:
1- Bacterio static and cidal according to its concentration.2- They bind to 50 S ribosomal subunits Translocation Protein synthesis.
---------------------------------------------------------------------------------------------------------------
Spectrum :
Similar to penicillin G but not identical:
- Gram +ve cocci
- Gram -ve cocci
- Gram +ve bacilli: Corynebacterium diphthriae.
- Some Grame -ve bacilli: H elicobacter , H. influenza, B. pertussis & Legionella.
- Others: Spirochetes - Chlamydia. - Mycoplasma pneumonia.
---------------------------------------------------------------------------------------------------------------Uses:
1- Drug of choice in:
Corynebactrial diphtheria - Chlamydial infection
Mycoplasma - Legionella & Bordetella pertussis.
2- Alternative to:
a- Penicillin in patients allergic to penicillin
b- Tetracyclines in Chlamydial infection of urogenital tract during pregnancy.
3- Prokinetic in diabetic gastroparesis
---------------------------------------------------------------------------------------------------------------
Adverse Effects:1- Epigastric pain & Diarrhea (most common)
2- Cholestatic jaundice esp. with esteolate ester (CI in liver disease)
3- Hypersensetivity reaction & skin rash
4- Drug Interactions: Cytochrome P 450 Metabolism of Theophylline, Warfarin
& Carbamazepine &Toxic concentrations.
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2-Clarythromycin Azithromycin-3 Similar to Erythromycin but:
1- Longer duration of action
[twice/day].
2- Less side effects
3- More effective especially against
Atypical Mycobacteria & H. pylori.
Similar to Erythromycin but:
1- Longer duration of action
[once/day].
2- Less side effects & not HME
3- More effective especially against
Atypical Mycobacteria & H.influenza.
NB.: New agents:
1- Ketolides: eg.: Telithromycin (Ketec):- Semisynthetic derivative of erythromycin
- Less bacterial resistance
- Side effects : visual disturbances – GIT dist.- Cardiac arrhythmia –
Pseudomembranous colitis – worsens myasthenia gravis
2- Oxazolidinones: eg.: Linezolid (Zyvox):- Less bacterial resistance
- Used in MRSA infections & Vancomycin resistant staph aureus & enterococci
infections (VRSA & VRE)
- Side effects: Thrombocytopeneaia & Neutropenia
Clindamycin (Dalacin-C)
It is a Lincosamide & structurally related to Macrolides
Pharmacokinetics:
1- Absorbed orally & Parenterally 2- Distributed all over the body but not CSF & Concentrated in bone & teeth.
3- Metabolized in liver and excreted in bile Enterohepatic circulation
Mechanism of action: Similar to Erythromycin Spectrum:
Similar to Penicillin G & Erythromycin. More effective against Anaerobes ,
but Mycobacteria & H. influenza are resistant.
Uses:1- Bone &Teeth infections.
2- Intra-abdominal Anaerobic infections
3- Locally in acne vulgaris
4- With Cephalosporins or Aminoglycosides in penetrating wounds& female genital
tract infection
Adverse Effects:1- Colitis: Fatal pseudomembranous colitis (C. difficile ) ttt by Vancomycin or
Metronidazole.
2- Liver function imparement3- Intestinal disturbances
4- Allergy & skin rash
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2-Aminoglycosides
[Streptomycin- Spectinomycin- Gentamicin- Amicacin- Neomycin-
Kanamycin- Tobramycin- Paromomycin]
Pharmacokinetics:1- Poorly absorbed orally as they are highly polar, so, given parentrally.
2- Distributed extra-cellularly,
- Concentrated in renal cortex and, endolymph & perilymph of inner ear
- Not pass BBB, however may pass placental barrier Fetal deafness.
3- Minimal Plasma protein binding: except streptomycin
4- Excreted mainly unchanged in urine by Passive glomerular filtration.
NB.: Aminoglycosides can be given once daily as they have concentration-dependent
killing & postantibiotic effect
Mechanism of action:1- Bacteri cidal Antibiotics2- They Protein Synthesis
- Aminoglycosides concentrate inside bacteria by 02 requiring active transport, so:
not effective against Anaerobes.
Transport is by B-Lactam antibiotic [But never mix in the same container]
- They bind to 30 S ribosomal subunit Misreading of m.RNA.
Spectrum:- Effective mainly against Gram -ve Bacilli including P. aeruginosa, Proteus &
Klebsiella. Also, active against some Gram +ve cocci e.g. -lactamase producing
Staph. aureus.
- Not active against streptococci & anaerobes (actinomyeces, bacteroides, clostridia &
spirochetes)
Side effects of Aminoglycosides:
1-Ototoxic :
a- Irriversible damage of the Vestibulo-auditory 8th
Cranial nerve.
b- with : 1- large doses , 2- long duration ,3- advanced age , 4- impaired renal function
5- concurrent use of frusemide & Salicylates .
2-Nephrotoxic:
a- Usually reversible.b- in : 1- Long use > 5 days
2- Poor kidney function
3- Concurrent use of frusemide .
3-Skeletal muscle Relaxation:
- Release of A.CH. & sensitivity of post-synaptic sites (Curare like)
- ttt by IV Ca Gluconate and Anti-Ch.E.e.g. Neostigmine
4-Allergy: e.g. contact dermatitis.
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Preparations & Uses :
A- Streptomycin: 1 g/ day IM.
- Bactericidal on Gram –ve bacilli & some +ve coccibut bacterio static in TB (intracellular organism)
- Uses: 1- IM in: T.B - Tularaemia - Brucillosis – Plague - Endocarditis.2- Orally to sterilize the bowel.
B-Gentamicin: 5mg /kg/day IM or IV.
Uses:1- Serious & Severe infection as Pneumonia, UTI, Osteomyelitis, Endocarditis &
Septicemia
2- P seudomonal infections3- MRSA (Melhicillin-resistant Staph aureus)
4- Topically in burns, wounds & skin lesions
C- Amikacin. Useful in Gentamicin-resistant infections
D- Tobramycin Similar to Gentamicin but more effective against P.aeruginosa.
E- Neomycin; - Used for local use mainly.
1- Orally: a- As intestinal antiseptic
b- Hepatic coma (Add Lactulose).
c- In hyperlipidemia
2- Topically on skin & mucous membranes
3- Inhalation in chest infections.
- Side effects: Malabsorption – Superinfection – Contact Dermatitis
F- Kanamycin : Similar Neomycin
G- Spectinomycin : In penicillin resistant Gonorrhea.
H- Paromomycin : Direct Amebicide
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3-Chloramphenicol & Thiamphenicol
Mechanism of action:
1-Bacteriostatic
2- It binds with 50S ribosomal subunit
Transpeptidation
Protein synthesis.
Spectrum: Broad spectrum. Affects Gram +ve & -v Bacteria & Rickettsia
Therapeutic Uses :
- Systemically: 1-Typhoid & Paratyphoid fever
2- Bacterial meningitis
3- Mixed aerobic and anaerobic infections.
4- Rickettsial infections (typhus & spotted fever)
- Topically in eye and ear infections.
Side effects:
1- Bone Marrow depression: which may be:
a- Reversible, dose-dependent
b- Irreversible, idiosyncratic, non-dose dependent, Fatal aplastic anemia.
2- Gray Baby Syndrome: In premature neonates, Chloramphenicol is poorly
metabolized Vomiting, flaccidity, hypothermia, shock, collapse & Gray
discoloration of skin.
3- GIT upsets, Superinfection & vit. K & B deficiency.
4- Drug interaction:a- HME Potentiate other drugs as: phenytoin, warfarin & tolbutamide.
b- Antagonizes the bactericidal action of Penicillins & Aminoglycosides
NB.: Treatment of Typhoid Fever :
A) Treatment of an Acute Attack:- First Choice Drugs:
a- Co-Trimoxazole.
b- Ceftriaxone & Cefoperazone.
C- Ciprofloxacin.
- Second Choice: Chloramphenicol & Ampicillin.
B) Typhoid Carrier:- Ampicillin & Co-trimoxazole
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Tetracycline-4
Preparations & Pharmacokinetics:
A) Slowly absorbed B ) Rapidly absorbed
Preparations:- Tetracycline- Oxytetracycline - Chlortetracyclin
- Demeclocycline
- Doxycycline- Minocycline .
Kinetics:1- Incompletely absorbed orally.
-Affected by food.
-Absorption is by: Milk, Ca, Mg, Fe &
Al Chelation of tetracyclines.
2- Distributed all over the body.-Pass BBB & Placenta
-Concentrated at sites of calcification
(Bone & Teeth).
3- Metabolized in liver by conjugation.
4- Excretion:
a- Mainly urinary
b- Bile Enterohepatic circulation.
c- Milk
1- Completely absorbed orally.
- NOT affected by food.
- Absorption is by: milk, Ca, Mg, Fe &
Al Chelation of tetracyclines.
2- Distributed all over the body.
3- Metabolized in liver by conjugation.
4- Excretion:
a- Minocycline: Urine, Bile, Milk
b- Doxycycline:
- Excreted in Bile
- Does not depend on renal excretion.
Allowed in renal patients.
NB.: Tigecycline: is a new synthetic tetracycline analogue, used IV & effective against
MRSA & VRSA infections
Mechanism of action of Tetracvclines:
1-Bacterio static
2- Protein synthesis: Concentrated in bacteria by specific transport proteins unique to
bacterial cytoplasmic membrane. Attach to 3O S ribosomal subunits Protein
synthesis
Spectrum:
Broad spectrum antibiotics:
- Affecting most Gram +ve & -ve bacteria
- Mycoplasma, Spirochetes, Chlamydia, Rickettsia
- Amoeba
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Uses of Tetracyclines :
1- Most of Gram +ve & -ve Bacterial Infections (Not TB or Typhoid) ,
[Mycoplasma , Clamydia , Rickettsia] ,
[ Amoeba & Cholera] ,
[Syphilis & Gonorrhea] ,[Brucellosis , Tularemia , Plague]
2- Skin infections & Eye infection: Topically
3- Demeclocycline to ADH in ttt of Syndrome of Inappropriate ADH secretion
(SIADH).
4- Minocycline in meningococcal carrier, but Rifampicin is better
Side effects & Toxicity of Tetracyclines :
1- Teeth & Bone Abnormalities: If tetracyctines are given during pregnancy orearly childhood, they bound to Ca
++& deposited in newly formed teeth & Bone:
a- Teeth : Permanent yellow-brown discoloration & Enamel dysplasia.b- Bone : Deformity & inhibition of growth.
2- Teratogenecity.
3- GIT irritation: Nausea, vomiting, epigastric pain, diarrhea, esophagitis &
haematemesis.4- Inhibit intestinal flora Vit B & K deficiency & Superinfection
(Pseudomembranous) colitis ttt by oral Vancomycin or Metronidazole.
5- Hepatotoxicity & Jaundice if Large doses specially during pregnancy
6- Nephrotoxicity specially if they used after the expiry date[Fanconi syndrome]
7- Hypersensitivity.
8- Photosensjtivity
9- Demeclocycline ADH Diabetes insipidus like syndrome.
10- Minocycline affect the CNS Vomiting, Vertigo, Dizziness.
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Mechanism of action:
1- Bacterio static.
PABA DHFA THFA.Sulfonamides Trimethoprim.
2- They Compete with PABA Dihydropteroate synthetase Folic acid
synthesis which is essential for synthesis of bacterial DNA & growth.
[animal cells utilize preformed folic acid.]
3- Synergism: by adding Trimethoprime which inhibits Dihydrofolate reductaseproducing Sequential block
4- Antagonism: by - PABA
- Procaine (converted to PABA)
- Pus
( NB): Mafenide is not affected by PABA or pus
Spectrum :a- Gram +ve & -ve bacteria (NOT Pseudomonas or Proteus).b- Chlamydia , Actinomyoces (Nocardiosis) & Pneumocystis carnii.
( NB): Sulfa stimulates the growth of Rickettsia).
Therapeutic Uses of Sulfa :
A) Infections:1- Systemically:
1- Meningococcal meningitis: ttt & Prophylaxis
2- Respiratory tract infection
3- Urinary tract infection:
4- Prophylaxis against Streptococcal infection (Sulfadiazine) in Rheumatic fever
5- Chlamydial infection & Nocardiosis
6- Bacillary dysentery : Poorly absorbed sulfa.
7- SMX + Trimethoprime
Co-trimoxazole (Antibacterial)- Sulphadoxine + Pyrimethamine Fansidar (Antimalarial)
- Sulphadiazine + Pyrimethamine Drug of choice in Toxoplasmosis
2- Topically: - Eye infections & Conjunctivitis: Sulfacetamide
- Skin burn & wounds : Mafenide & Sliver Sulfadiazine.
B) Inflammations: Ulcerative cotitis & Rhematoid artheritis: Sutfasalazine
Dihydropteroate-synthetase Dihydrofolate Reductase
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Quinolones-2
Classification & Spectrum:
First Generations Second Generation Third Generation Fourth Generation
Spectrum:Gram -ve organisms
(but not
Pseudomonas)
- Gram-ve organisms(including
Pseudomonas)
- some gram +ve
organisms ( but not
Streptococcus
pneumoniae)
- some atypical pathogens
Same as for 2nd
generation plus:
- expanded gram
+ve coverage
(penicillin-sensitive
and penicillin-
resistant S.
pneumoniae)
- expanded atypicalpathogens
Same as for 3rd
generation plus:
broad anaerobic
coverage
Preparations:
- Nalidixic acid
- Cinoxacin
Useful in
Prevention and ttt of
U.T.I
- N orfloxacin
- O floxacin
- Pefloxacin
- Lomefloxacin
- C iprofloxacin
-Levofloxacin
- Gatifloxacin
- Sparfloxacin
- Moxifloxacin
Trofloxacin
Fluoroquinolones 60 times more potent than quinolones
Pharmacokinetics:
1- Absorbed orally. Bioavailability 80% - 90%.
2- Distributed all-over the body & concentrated intracellularly esp. prostatic tissue,
Kidney, Macrophages & PMNLs, but Low CSF levels 3- Metabolized in liver.
4- Excretion: in urine & bile
NB: Trofloxacin has long t1/2 given once /day, but may cause serious liver injury
Mechanism of action:1- Bactericidal
2-They enter the bacteria by passive diffusion
Bacterial DNA gyrase (Topoisomerase II) enzyme
Supercoiling of DNA DNA Replication
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Uses:1- UTI & Prostatitis
2- Sexually transmitted diseases eg Gonorrhea & Chlamydia [ Not syphilis]
3- Respiratory tract infections
4- GIT infections: Diarrhea - Typhoid fever & Intra-abdominal infections.
5- Osteomyelitis.6- Septicemia.
7- Multidrug resistant TB.
Adverse Effects:
1- Hypersensetivity
2- Photosensitivity, use sunscreens & sun blocks.
3- Nephrotoxic
4- Hepatotoxic: with Troflouxacin
5- Chondrolytic & Reversible Arthropathy , joint swelling & damage of
growing cartilage
Contraindicated in: pregnancy, lactation & pre-pubertal children.6- Confusion, Headache & dizziness Avoid driving.
Seizures if used with NSAID (eg.: Fenoprofen) Avoid in Epileptics.7- Crystaluria.
8- Disturbance of GIT & Superinfection.
9- Drug Interactions:
a- They are HME inhibitors Metabolism of Theophylline, Warfarin &
Sulfonylureas.
b- HME inhibitors as Cimetidine metabolism of Fluoroquinolones
c- Sucralfate & Antacids their absorption
e- With NSAID & Theophyllin Seizures
NB.: Benefits of antibiotic combinations:1- Synergise the action
2- Broaden the spectrum
3- Delay development of bacterial resistance
4-
Treatment of mixed bacterial infections5- Treatment of serious infections before culture & sensitivity is done
NB.: avoid the use of static with cidal drugs
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Mechanism1- Bacteri cidal
2- DNA dependant–RNA.
Polymerase enz. synthesis
of m. RNA
3- Spectrum: T.B – leprosyGm-ve & Gm+ve
Chlamydia & Pox virus
1- Tuberculo static & cidal
2- * Mycolic acid synthesis
present in cell wall of T.B
* utilization of vit. B6 in
T.B3- Spectrum: T.B only
Uses1- T.B: in combination with INH
2- Leprosy
3- Resistant bacterial infections e.g:
staph4- Drug of choice in chemo-
prophylaxis of meningococcalmeningitis
T.B: Treatment in combination with
Rifampicin & Chemoprophylaxis in
children exposed to active patients
Side effects1- *Red discoloration of urine &
all secretions
2- HME Inducer Metabolism
actions of oral anticoag. -
Hypoglycemic-contraceptives
3- Fever – Flu-like syndrome
4- Ataxia- Headache - Confusion
5-
GI.T disturbances6- Hepatotoxic & Jaundice
1- HME I nhibitor
metabolism actions &
toxicity of drugs as phenytoin.
2- MAO I nhibitor with food
containing tyramine
Hypertension
3- *PolyNeuritisesp. in slow
acetylators , prevented &
treated by Pyridoxine (vit B6)
4-
Hypersensitivity: SLE likesyndrome
5- *Hepatotoxic esp. in Rapid
acetylators
6- Haemolysis in patients with
G.6.P.D deficiency
NB.: Rifabutin & Rifapentine: as rifampin but, less HME inducer
2) TREATMENT OF LEPROSY
Drug combination for at least 2 years:
Dopson {sulphon group} + Rifampicin + Clofazimine.
Thalidomide may be used in severe cases
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Chemotherapy
292
ANTI-AMOEBIC DRUGS
(1) Tissue Amebicides:1- Nitroimidazoles: Metronidazole - Tinidazole - Ornidazole
2- Chloroquine
3- Emetine & Dehydroemetine
(2) Luminal Amicides:1- Diloxanide Furoate
2- Halogenated Hydroxy-quinoline: - Di-iodo- Hydroxy-quinoline
- Iodo-chloro- Hydroxy-quinoline -
3- Antibiotics: - Tetracycline
- Paromomycin
1- Diloxanide Furoate
- Kinetic: - Well absorbed orally & Hydrolyzed in Gut Mucosa
- Actions & uses:- Luminal amebicidal [Drug of choice in Asymptomatic intestinal carriers]
- S.E: 1- Dry mouth & Flatulence
2- Urticaria & Pruritis
3- Not used in: - Pregnancy & Children less than 2yrs
2- Halogenated Hydroxyquinolines
(Di-iod …& Iodo-chloro… [Enterovioform])
- Luminal arebicidal: Motile & cyst- Enterovioform used in: - Trichomonas Vaginalis - Fungal infection
- S.E: 1-GIT dist. 2- Headache 3-Thyroid enlargement 4- Hepatic dysfunction
5- Enterovioform SMON [Subacute myelo optic neuritis in Japanese]
3- Paromomycin flora needed for ameba & direct amoebicide
Trophozoit
TrophozoitTrophozoitcyst
Luminal amebicide Tissue amebicide
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293
4- Metronidazole
- Kinetic:- Well absorbed orally
- Distributed all over the body
- Concentrated in: - CSF – Saliva – Milk - Vaginal secretion - seminal fluid.- Metabolized in liver
- Excreted in urine
- Mechanism:
Metronidazole active metabolite which bind to DNA nucleic a.
synthesis
- Uses:1- Amoebiasis: Intestinal & Hepatic
2- Giardiasis
3- Trichomoniasis4- Anaerobic infections (esp. H. Pylori in peptic ulcer & C. diffecile in
pseudomembranous colitis)
- Side effects.1- Allergy
2- GIT dist. & Metallic taste
3- CNS: Headache – Dizziness -Vertigo
4- Neutropenia
5- Disulfiram like reaction
NB: Tinidazole: as Metronidazole but given once\day
5- Emetine & Dehydro-emetine
- Kinetic: * - I.M & S.C - Never I.V
- Concentrated in liver
- Actions:- Tissue amebicidal against Trophozoite ( No affect on cysts )
- S.E:1- GIT disturbance
2- Cardiotoxic
3- CNS: Headache & Peripheral neuritis4- Myopathy & Joint pain
Reduced by
Ferrodoxin
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ANTI–MALARIAL DRUGS
1) 4- amiono quinoline : Chloroquine & Amodiaquine .
2) 8- aminoquinoline: Primaqine .3) Dihidrofolic acid reductase enz . inhibitors: Proguanil & Pyrimethamine .
4) Quinine. 5) Mefloquine . 6) Quinacrine.7) Halofantrine
8) Artemesine & related compounds
NB.: P. falciparum & P. malaria: have no exoerythrocytic stage
..
Trophozoit
RBCs
Blood shizont
Clinical cure orSuppressive Prophylaxis:
1- 4-aminoquiline
2- Quinine
3- Pro. &Pyri.
.
.
Gametocytes
Sporontozoites
Prevent transmittion:1- G. Primaquine
2- S. Pro. & Pyri.
2ry tissue
shizont
relapse:-AntiPrimaquine
1ry tissue
shizont
Causal
rophylaxis:P
1- Pro. & Pyri.
2- Primaquine
Merozoite
Sporozoites
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299
3- Azoles (Imidazoles & Triazoles) :
1- Ketoconazole (Nizoral ):- Kinetic: - Given orally [Food-antacids & cimitdine impair the absorption]
& Topically as shampoos in cases of dandruff
- Dos not pass BBB- Mechanism: Block cytochrome P450 which is responsible for
demethylation of lanosterol into ergosterol ergosterol
Synthesis disrupts membrane function.
[ Additive affect between (ketoconazole & flucysine) & ( Amphotericin B &
Flucytosine) & antagonism between (ketoconazole & amphotericin) ]
- Spectrum: fungi static or fungi cidal broad spectrum antifungal
- S.E: 1- Allergy
2- GIT disturbances
3- Gynecomastia & impotence (as ketoconazole androgen & adrenal
steroid synthesis)
4- Hepatic dysfunction
5- HME
6- Toxicity of Cyclosporin
2- Itraconazole: As kataconazole but wider spectrum & less S.E
3- Fluconazole (Diflucane): As ketocanazole but:
1- Given orally & I.V
2- Penetrate CNS
(Drug of choice in fungal meningitis & in immuno-compromised patients)
3- Less S.E & no endocrine effects.
4- Echinocandins: (eg.: Capsofangin)- Kinetic: - not absorbed orally, given IV
- highly bound to plasma protein
- Mechanism:
synthesis of a glucose polymer present in the structure of cell wall- Spectrum: Fungi cidal against Aspergillus & candida
- S.E.: Phlepitis – Flush due to histamine release
Ketoconazole
Lanosterol ErgosterolP450
Demethylation
-
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2- Systemic anti-fungal drugs for mucocutaneous infectious:
1- Griseofulvin:
- Kinetic:. - Well absorbed orally
-
Concentrated in keratinized tissues- Extensively metabolized & excreted in urine
- Mechanism: Penetrates the fungal cell by energy dependent process Binds with
microtubules mitotic cell devision
- Spectrum: Fungi static against dermatophytes only
- N.B: it is fungistatic & keratophylic accumulates in newly synthesized keratin
containing tissues making them unsuitable for fungal growth , so, ttt must
continue until normal tissue replaces infected one (weeks or months )
- S.E : 1- GIT disturbances
2- Teratogenicity
3- Headache4- Hepatotoxocity
5- HME
6- Contraindicated in Porphyria
2- Terbinafine (Lamizil):
- ergosterol synthesis but does not affect P450
- It is fungi cidal for dermatophytoses especially onychomycosis
3- Topical anti fungal drugs:
1- Nystatin (Mycostatin): - It is a polyene antibiotic as amphotericin B but;
- Used only topically due to systemic toxicity (orally for oral & intestinal
candidiasis & locally on skin or Vagina)
2- Topical Azoles: [Miconazole – Econazole – Clotrimazole]As ketoconazole but used topically only due to toxicity
3- Tolnaftate
Whitfield ointment (Benzoic a. + salicylic a.)
Undecylenic a.
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1- Inhibition of attachment & Penetration
1- Gamma Globulin:Coates & neutralizes viruses Preventing their attachment & penetration
2- Amantadine & Rimantadine:- Mechanism: Attachment – uncoating & release of new viruses
- Used in prophylaxis of influenza A not B
- S.E: 1- GIT disturbances
2- C.V.S: ankle oedema
3- CNS: Insomnia – Dizziness – Hallucination
2- Inhibition of transcription &nucleic acid synthesis:
A-DNA Polymerase inhibitors:
1- Acyclovir:
- Guanosine derivative & Prodrug Triphosphate nucleotide,
which inhibit DNA polymerase enzyme
- Uses: Herpes simplex virus (HSV) & Varicella zoster virus (VZV)
not active againest Epestien Barr Virus (EBV) & Cytomegalovirus (CMV)
- S.E: 1- GIT disturbances
2- Renal dysfunction
3- Local irritation
2- Penciclovir:- As Acyclovir but used topically only
3- Gancyclovir:- As acyclovir but it is the drug of choice in CMV, which is common in
immunocompromised patients
4- Ribavirin (Tribavirin)- As acyclovir & May synthesis of viral m.RNA
- Uses: broad spectrum, effective against a wide range of RNA & DNA viruses
esp. Respiratory viral infection & used with interferon in hepatitis C virus
- S.E: 1- Hepatotoxic2- Anemia
3- Teratogenic
5- Idoxuridine:- Thymidine analogue used topically only in Herpes simplex virus.
- Highly toxic So, not used systemically
6- Vidarabine:- Adenosine derivative selectively DNA Polymeraz enz.
- Used : I.V or topically in HSV & VZV
7- Foscarent: Active against CMV
Phosphorylaion byViral thymidine kinase
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303
B- Reverse transcriptase inhibitors (RTIs): a- Nucleoside:- Zidovudine – Dideoxy inosine (DDI) – Dideoxy cytidine (DDC)
- Thymidine analogues & Prodrugs activated inside cells & RNA dependent
DNA Polymerase [Reverse Transcriptase }
- S.E: 1- Bone marrow depression2- Headache
3- toxicity by: Probenicid – Paracetamol- Indomethacin -Cimitidine
b- Non-nucleoside: as Nevirapine & Efavirenz
3-Inhibition of post-translation events [Protease inhibitors]
- Ex: Squinavir – Ritonavir – Indinavir
- Mechanism: HIV protease enz.which is essentials for conversion of
translated inert proteins into functional & structural proteins
- S.E: 1- G.I.T disturbances
2- Thrombocytopenia3- Hyperbilirubinemia
4- Nephrolithiasis with Indinavir
4-Inhibition of Assembly - eg. : Rifampicin inhibit Poxvirus
5- Inhibition of Release: (Neuroaminidase inhibitors):e.g. : Zanamivir & Oseltamivir are given by inhalation in ttt of influenza A (including
Avian influenza) or B
6- Immunomodulators : (Interferons):• Endogenous proteins which exert non specific antiviral action esp. & types
• Mechanism: Penetration – uncoating – m. RNA synthesis – translation –
assembly & release
• They are 3 types: - - interferons & used for chronic hepatitis B & C
NB.: Pegylated interferones has longer duration & given once weekly
• S.E: a. Influenza like syndrome
b. Anorexia & weight loss
c. Alopecia
d. Bone marrow depressione. Confusion & Seizures.
------------------------------------------------------------------------------------------------------- N.B: 1- Drugs for AIDS (HIV) [Antiretroviral agents]:
1- Reverse transcriptase 2- Protease enz.
2- Drugs for Hepatitis viruses esp. HCV:1- Reverse transcriptase 2- Ribavirine
3- Gamma globulin 4- Interferons
NB.: Standard treatment of chronic HCV:
Once weekly Pegylated INF alpha + daily oral Ribavirin
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Anti-Bilharizial Drugs
NiridazoleMetrifonateOxamniquinePraziquantil
Egg
deposition
Organophosphorus
compound with
anti-Ch.E
Activity
Depolarization
Block & paralysis
- Bind DNA
- Egg deposition
Ca++
inaflux
Spastic
ParalysisMechanism
Haematobium.Haematobium
only
Mansoni only-Mansoni &
haematobium
(40mg / kg single)
-Taenia
- H. Nana
- Heterophytes
Spectrum
1- CNS: -headache
-vertigo
2- GIT disturbance
3- effect of
succinylcholine
1- CNS: - headache
- dizziness
2- GIT disturbance
3- Orange red
urine &
protinuria4- Fever.
1- CNS: - headache
- dizziness
2- GIT disturbance
3- Arthritis &
Myalgia
4- Fever & Pruritis
S.E:
- pregnancy
- Epilepsy.
- pregnancy- pregnancy
- Epilepsy
- pregnancy
- child < 4yC.I
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ANTHELMENTHICS
Tretment of Leishmaniasis:- Sodium stibogluconate IM & IV- Pentamidine isethionate IM
- Amphotericin B
Treatment of Filariasis:
- - Diethylcarbamazine (Heterzan)
- - Ivermectin
1- Mebendazole [ Glucose uptake] 2- Albendazole
3- Pyrental pamoate[Depolarizing N.Mblock] 4- Levamizole[Depolarizing N.Mblock]
5- Piprazine [Curare like]
(1) Ascaris:
(Round worm)
1- Mebendazole
2- Albendazole 3- Pyrental pamoate
4- Levamizole
(2) Ankylostoma:
(Hook worms)
1- Mahendazole
2- Albendezole 3- Pyrental pamoate
4- Pyrivinium
(3) Enterobius:
(Pin worms, oxyuris)
1- Mebendazole2- Albendezole3- Thiabendezole
(4)Strongyloides:
(Thread worm)
1- Praziquantel
2- Niclosamide (5) Tainia sagineta
1- Praziquantel2- Atebrine
(6) Tainia Solium
1- Praziquantel
2- Niclosamide (7) Hymenolepis nana
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Chemotherapy
CAUSES OF FAILURE OF ANTIMICROBIAL THERAPY:
1- Organism factors:1. Development of resistance which may be:
a- Non-genetic: as Mycoplasma has no peptidoglycan cell wall
resistant to -lactam antibioticsb- Genetic: Which may be Chromosomal (mutation) or extra-
chromosomal
2. Development of Superinfection: Superinfection is an isolation of new
pathogen resistant to the previous antimicrobial regimen (as candidiasis &
pseudomembranous colitis with broad spectrum oral antibiotics)
2- Drug factors:1. Mono-therapy may be insufficient for some infections which may require
two drug therapy for successful outcome as enterococcal endocarditis &
certain psudomonous aeroginosa infections
2. Multiple-therapy may cause antagonism as Imepenem with Pipracillin &
Ketoconazole with Amphotericin B
3. Inadequate duration of therapy: women with 1st
time non-complicated
cystitis may respond to single oral antibiotic, but recurrent UT infection
requires longer duration of therapy
4. Subtherapeutic dose: which may be due to:
a- Inadequate dose
b- Inadequate absorption (eg.: ciprofloxacin with antacid or sucralfate)
3- Patient factors:1. Diseases: as in
- Immunodeficiency
- Diabetes (Delayed healing of wounds & peripheral vascularinsufficiency delivery of antibiotic to the site of infection)
2. Infection of Prosthetic material as prosthetic cardiac valves & hip
replacement They should be removed
3. Site of infection: antimicrobial penetration to the site of infection may be
inadequate as in prostatitis & meningitis