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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


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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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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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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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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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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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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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

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