CHEMOTHERAPY - Fundamental Pharmacy...[No effect on intestinal flora.] 3- Amoxycillin Similar to Ampicillin but: a- Better oral absorption& not affected by food b- Longer duration

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CHEMOTHERAPY

�������������

����������������� ������� ������� ���������

1- Bactericidal: �-lactam antibiotics, Polymixines, Quinolones, Aminoglycosides , Rifampicin

2- Bacteriostatic: Sulphonamides , Chloramphenicol , Tetracyclines 3- Bcteriostatic& cidal: according to concentration as: Erythromycin & Isoniazid

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Classification of Bactericidal drugs: 1- Concentration dependant killing: (eg.: Aminoglycosides & Quinolones)

���� Drug concentration �� the rate & extent of killing 2- Time dependant killing: (eg.: �-lactam antibiotics)

The rate & extent of killing does not depend on drug conc., but the bactericidal effect continues as long as its conc. above the MBC (minimal bactericidal conc.)

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

N.B.: Postantibiotic effect (PAE): - Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent - Most antimicrobials have PAE against gm +ve cocci - Carbapenems & agents that � protein or DNA synthesis have PAE against gm –ve bacilli ����������������� ��������������������� ���������

1-���� Synthesis of bacterial cell wall: a- Cycloserine: � Formation of di-d-alanine b- Fosfomycin: � Formation of N-acetyl cysteine c- Vancomycin , Teicloplanin & Bacitracin: �Elongation of peptidoglycan d- �-Lactam antibiotics: � last step of cell wall synthesis. [�Transpeptidase enz. responsible for cross linking of the long peptidoglycan]

2- ���� Permeability of cytoplasmic membrane ���� cell damage: eg.: Amphotericin & Nystatin (antifungal), Daptomycin & Polymexin. 3- ���� Proteine synthesis through:

a- � Formation of m.RNA [� RNA polymerase] : eg.: Rifampicin b- Binding with 30S ribosomal subunit of bacteria eg.:Aminoglycoside , Tetracycline c- Binding with 50S ribosomal subunit of bacteria eg.:Chloramphenicol , Erythromycin , Lincosamides

4- ���� Nucleic acid metabolism: a- Folate antagonists: - Compete with PABA :eg.: Sulphonamides -� Dihydrofolate reductase enz.: eg.: Trimethoprime & Pyrimethamine b-� DNA: -Antiviral & anticancer –Griseofulvine -Metronidazole & Chloroquine -Quinolones [� DNA gyrase enz.] c- � RNA eg.: Rifampicine [� RNA polymerase enz.].

------------------------------------------------------------------------------------------------------------------------ NB.: Mycoplasma lack a cell wall, so they are resistant to cell wall inhibitors

AT

CEL

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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+ Pteridine

Sulpha Dihydropteroate synthase

Folic a.

Trimethoprim & Pyrimethamine

reductase efolat Dihydro

DHF acid

Anti-viral & cancer Griseofulvin Metronidazole Chloroquine

THF acid (Foloinic a.)

Purines

DNA

Quinolones

Rifampicin

gyrase DNA

Super-coiled DNA

m-RNA

polymerase RNA

-

-

-

-

-

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 & IV 2-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 bile �Enterohepatic 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: Clostridia: tetani (Tetanus) & perfringens (Gas gangrene) - Corynebacterium 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, Haemophilus influenza & Helicobacter pylori. C-Extendgd Spectrum (Antipseudomonal) Penicillins:

- As broad spectrum + Pseudomonas aerugenosa, Proteus & Klebsieilla 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 acid b- 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 with infective mononucleosis & taking allopurinol

2- Jarisch-Herxheimer reactions : a- Febrile reaction accompanied with exacerbation of local syphilis on 1st

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 aureus 4- 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 & Listeria

monocytogenes

Classification:

1st Generations 2nd Generation 3rd Generation 4th Generation

Spectrum: Broad spectrum. Active mainly against gram + ve organisms

Broad spectrum. Similar to 1st generation but less active on Gram +ve & more on Gram –ve

Broad spectrum similar to 2nd generation 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 meningitis

Passes BBB � useful in meningitis

Preparations: Oral: Cephalexin Cephadroxil 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: Cefepime - Cefpirome

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 be

prevented 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 a dipeptidase 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- Nephrotoxic c- Rapid infusion �Histamine 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 2nd line 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. pseudomonus 3- Not absorbed orally & nephrotoxic , so used ONLY locally

Daptomycin It 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- Bacteriostatic 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: Helicobacter, 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 imparement 3- 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- Bactericidal Antibiotics 2- 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 cocci

but bacteriostatic 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- Pseudomonal infections 3- 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-Bacteriostatic 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 or early 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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4-Inhibitors of nucleic acid synthesis

1-Sulfonamides

• Synthetic chemotherapeutic agent,derived from P-aminobenzene sulfonamide (Sulfanilamide). • Obtained by substitution in Amide (N1) or Amino (N4) groups.

Classification of Sulphonamides :

phonamides for Systemic UseSul -1 Sulphonamides for Topical Use -2

:Rapidly absorbed-1 :Poorly absorbed-2 A) Short Acting: -Sulphadiazine -Sulohamerazine -Sulphisoxazole B) Intermediate Acting: Sulphamethoxazole (SMX) C) Long Acting: -Sulphamethoxydazine -Sulphadoxine

-Sulphaguanidine -Sulphathalidine -Sulphasuccidine -Sulphasalazine (Salazopyrine) Useful in Ulcertaive colitis & RA

Pharmacokinetics;

1- Absorbtion: Rapidly absorbed sulfa are well absorbed orally 2- Distribution:

- Distributed all over the body & pass BBB and placental barriers. - Highly bound to plasma proteins ���� displace billirubin ���� Kernictrus in neonates.

4- Acetylated in liver (Acetylated sulfa ���� Inactive & Insoluble in acid urine) 5- Excretion:

a- Excreted & concentrated in urine mainly unchanged NB.: Acetylated sulfa may produce Crystaluria, Prevented by plenty (excess) fluid intake & Alkalinization of urine.

b - Excreted in milk. c- Poorly absorbed sulfa are excreted in stool.

N1 N4

1- Sulphacetamide :

Eye infections 2- Silver Sulphadiazine: Skin cream 3- Mafenide: Skin cream & powder

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Mechanism of action:

1- Bacteriostatic.

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 reductase producing 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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286

Adverse Effects of Sulfonamides:

1- Allergy &Hypersensitivity reactions: a- Manifestated by fever, rash & photosensitivity b- Cross-Allergy with other Sulfonamides e.g.: Thiazides, Diazoxide , Frusemide,

Bumetanide & Sulfonylureas. 2- Blood dyscrasias:

a- Hemplysis in patients with G6PD deficiency. b- Bone marrow depression (aplastic anemia, agranulocytosis). 3- Crystaluria: Avoided by: - plenty fluid intake,

- alkalinization of urine or - the use of sulphonamide mixture (Tripple sulpha � diazine + merazine + methazine)

4- Drug interactions: a- Displace Warfarin & Tolbutamide ���� Initial increase in their activity. b- Displace billirubin ���� Kernictrus. Avoid during pregnancy & lactation. c-Methenamine (Urinary antiseptic) releases formaldehyde����Inactivates sulfa

5-Disturbance of GIT & Superinfection.

6- Nephrotoxicity & Hepatotoxicity.

Trimethoprim (TMP)

-Kinetic: As SMX ,but it is a weak base ���� trapped in acidic prostatic fluid -Mechanism: Inhibits DHFR �������� conversion of DHFA into THFA (Folinic Acid) -Uses: 1- Urinary tract infections & Prostatitis. 2- Respiratory tract infections. -Adverse Effect: Megaloplastic anemia- Prevented and treated by Folinic acid NB.: Trimetrexate: 1500 times stronger than Trimethoprime

Co-trimoxazole

- Trimethoprim (TMP, 80 mg) + Sulfamethoxazole (SMX, 400 mg) =1:5. - Mechanism of action: 1- They produce Sequential Block in the synthesis of folinic acid & DNA ����synergism

& less incidence to develop resistance 2- More potent, wider spectrum & less bacterial resistance than each drug alone. - Uses: as sulfa esp.: 1- Respiratory tract infection

2- Urinary tract infection (UTI) & Prostatitis 3- Drug of choice in Pneumocystis jiroveci (carinii)

- Adverse Effects: Both Sulfa + TMP

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287

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 atypical pathogens

Same as for 3rd generation plus: broad anaerobic coverage

Preparations: - Nalidixic acid - Cinoxacin Useful in Prevention and ttt of U.T.I

- Norfloxacin - Ofloxacin - Pefloxacin - Lomefloxacin - Ciprofloxacin

-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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288

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 infections 5- Treatment of serious infections before culture & sensitivity is done

NB.: avoid the use of static with cidal drugs

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289

TREATMENT OF URINARY TRACT INFECTION (UTI)

1-Antimicrobials:

1- Sulfisoxazole – Cotrimoxazole 2- Penicillins: (Amoxyacillin – Ampicillin) & Cephalosporins 3- Aminoglycosides 4- Chloramphenicol – Tetracycline 5- Quinolones: Norfloxacin

2-Urinary antiseptics:

- They disinfect the urine & have high conc.in urine & low conc. In blood 1-Methinamine : orally in acid Formaldehyde (Toxic to bacteria esp.E.coli )

- Methinamine Urine liver Amonia Urea (excreted by kidney) 1- Its efficacy is � by acidifying agents e.g Mandelic acid 2- Bacteria which split urea into ammonia (e.g Proteus) �alkalinization of urine, are resistant 3- Sulfonamides form insoluble compound with formaldehyde, so, they are not used with methinamine 4- Contraindicated in liver or renal failure (Ammonia Encephalopatly)

2- Nitrofurantoin: orally In acid urine - Nitrofurantoin: Agent which damage DNA in bacteria - Acidification of urine � � its activity

- S.E: 1- GIT dist. 2- Allergy

3-Idiosyncrasy: Haemolysis in patient with G.6.P.D� 4-Brownish discoloration of urine 5-Headache & neuropathy 6-Pneumonitis & interstitial fibrosis

3- Nalidixic acid & Cinoxacin: orally Quinaolone derivatives, little affected by urinary pH, used only in UTI.

3-Alteration of urinary pH:

1- Acid urine � � efficacy of: Penicillins – Tetracycline Methenamine – Nitrofurantoin

2- Alkaline urine �� efficacy of: Sulfa – Aminoglycosides – Erythromycin �� growth of some organisms eg: E.coli �Relieve dysuria

Chemotherapy

290

ANTI-MYCOBACTERIA

1) ANTI- TUBERCULOUS DRUGS • First line drugs: [Drugs with high efficacy & acceptable side effects]

1- Rifampicin (Rifampin) (Rimactane) 2- Isoniazid (INH): [Hydrazine of IsoNicotinic acid] 3- Pyrazenamide :

Side effects: a- Hepatotoxic b- Hyperuricemia 4- Ethambutol:

Side effects: a- Optic neuritis b- Hyperuricemia 5- Streptomycin

----------------------------------------------------------------------------------------------------------------------- • Second line Drugs: [Less effective & More toxic]

1- Para-amino-Salicylic acid {PAS}: Side effects: a- Allergy b- GIT disturbance c- Hepatotoxic d- Nephrotoxic e- � Thyroid

2- Ethionamide: Side effects: a- Allergy b- GIT disturbance c- Heptotoxic

3- Cycloserine a- Allergy b- GIT disturbance c- CNS �& psychosis

4- Ciprofloxacin , Ofloxacin & Levofloxacin: Quinolones used mainly in resistant strains

5- Clofazimine: a phenazine dye 6- Clarithromycin: Macrolid antibiotic 7- Linezolid 8- Kanamycin ,Amikacin & Viomycin: Aminoglycoside antibiotics

• Regimens:

1- Short regimen: 9 months � Rifampicin + INH 2- Very short regimen: 6 months � Rifampicin + INH (+ Pyrazinamide & Ethambulol for the 1st 2 months only)

Rifampicin

Isoniazid (INH)

Kinetics 1- Well absorbed orally 2- Distributed all over the body 3- Deacetylated in Liver 4- Excreted in : * Bile � Enterohepatic circulation * Urine � Red discoloration

1- Well absorbed orally 2- Distributed all over the body 3- Acetylated in liver (Slow & Rapid

acetylates) 4- Excreted in urine.

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291

Mechanism 1- Bactericidal 2- � DNA dependant–RNA.

Polymerase enz. � � synthesis of m. RNA

3- Spectrum: T.B – leprosy Gm-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.B

3- Spectrum: T.B only

Uses 1- T.B: in combination with INH 2- Leprosy 3- Resistant bacterial infections e.g:

staph 4- Drug of choice in chemo-

prophylaxis of meningococcal meningitis

T.B: Treatment in combination with Rifampicin & Chemoprophylaxis in children exposed to active patients

Side effects 1- *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 disturbances 6- Hepatotoxic & Jaundice

1- HME Inhibitor �� metabolism �� actions & toxicity of drugs as phenytoin.

2- MAO Inhibitor�with food containing tyramine � Hypertension

3- *PolyNeuritis �esp. in slow acetylators , prevented & treated by Pyridoxine (vit B6)

4- Hypersensitivity: SLE like syndrome

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

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

Trophozoit Trophozoit cyst

Luminal amebicide Tissue amebicide

Chemotherapy

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- Trichomoniasis 4- 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 neuritis 4- Myopathy & Joint pain

Reduced by Ferrodoxin

Chemotherapy

294

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 or Suppressive Prophylaxis: 1- 4-aminoquiline 2- Quinine 3- Pro. &Pyri.

.

.

Gametocytes

Sporontozoites

Prevent transmittion: 1- G. � Primaquine 2- S. � Pro. & Pyri.

2ry tissue shizont

relapse:-Anti Primaquine

1ry tissue shizont

Causal rophylaxis:P

1- Pro. & Pyri. 2- Primaquine

Merozoite

Sporozoites

Chemotherapy

295

Antimalarial drugs:

1- Causal prophylaxis : [lry tissue schizonticidal ] : a- Proguanil & Pyrimethamie

b-Primaquine 2- Anti – relapse: [2ry tissue schizonticidal ]: Primaquine 3- Clinical cure or suppressive prophylaxis: [blood schizonticidal ] :

a- 4- aminoquinoline b- Proguanil & Pyrimethamire c- Quinine

N.B blood schizonticidal may cause radical cure in P.folciparum & P. malarie as they have no exoerythrocytic stage 4- Preventing transmission: [Acting on sexual forms] 1-Gametocidal : Primaquine 2- Sporontocidal : Proguanil & Pyrimethamine

Chemotherapy

296

Chemotherapy

297

Chemotherapy

298

ANTIFUNGAL DRUGS

1- Systemic anti-fungal drugs for systemic infection

1- Amphotericin B: - Polyene antibiotic [Macrolide] - Kinetic: - Poorly absorbed orally, so, given I.V infusion, intrathecal or topically - Poor penetration to C.S.F - Mechanism: Binds to ergosterol in the cell membrane forming pores through

which electrolytes & cell constituents leak from the cell � cell death [Human cell membrane contains cholesterol not ergosterol]

- Spectrum: Broad spectrum antifungal & it is either fungicidal or fungistatic - S.E: 1- Low therapeutic index [start by small dose]

2- Fever, chills & convulsions 3- Hypotension & Hypokalemia 4- Anemia & Anaphylaxis 5- Irritant � Thrombophlebitis 6- Nephrotoxic

2- Flucytosine: - Synthetic pyrimidine antimetabolite. - Kinetic: Absorbed orally – Passes BBB - Mechanism: enters the fungal cell via cytosine specific permease enz., where it is converted to 5. Fluorouracil which ���� DNA synthesis - Spectrum: Fungistatic, combined with Amphotericin B for systemic mycosis &

used alone for subcutaneous chromomycosis - S.E: 1- GIT disturbance & severe entero-colitis

2- Hepatic dysfunction 3- Neutropenia & thrombocytopenia

Antifungal drugs

for Systemic antifungal

mucocutaneous infections

1- Griseofulvin: (static) 2- Terbinafine: (cidal)

Topical antifungal

1- Nystatin 2- Topical azoles 3- Others:

- Tolnafate - Undecylinic a. - Whitefeild ointment

Systemic antifungal For systemic infections

1- Amphotricin B (static & cidal) 2- Flucytosine (static) 3- Azoles: (static & cidal)

- Ketoconazole - Itraconazole - Fluconazole

4- Echinocandins: (cidal) eg.: Capsofangin

Amphotericin B

Molecules

Flucytosine

Flucytosine

5-FU � DNA synth.

Chemotherapy

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: fungistatic or fungicidal 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: Fungicidal against Aspergillus & candida - S.E.: Phlepitis – Flush due to histamine release

Ketoconazole

Lanosterol Ergosterol P450 Demethylation

-

Chemotherapy

300

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: Fungistatic 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- Headache 4- Hepatotoxocity 5- � HME 6- Contraindicated in Porphyria

2- Terbinafine (Lamizil):

- � ergosterol synthesis but does not affect P450 - It is fungicidal 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.

Chemotherapy

301

ANTIVIRAL DRUGS Viral cycle:

NB.: In HIV (which is RNA virus) , after uncoating, DNA is synthesized from viral RNA by viral reverse transcriptase enzyme

1- Attachment

8- Assembly

9- Release (by Neuroaminidase enz.)

2- Penetration

3- Uncoating & transfer of viral DNA to nucleus & integrated into

host DNA by integrase enz.

4- Early transcription into

viral m-RNA

5- Early translation of m-RNA into enz. needed for DNA synthesis (DNA polymerase enz)

6- Synthesis of viral DNA & late

transcription of viral m-RNA

7- Late translation into

viral prot.

In HIV (inert prot.)

Functional prot.

Protease enz.

1

2

5

4 3

Chemotherapy

302

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- Hepatotoxic 2- ������������������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 by Viral thymidine kinase

Chemotherapy

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 depression

2- 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- Thrombocytopenia 3- 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 depression e. 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

Chemotherapy

304

Anti-Bilharizial Drugs

Niridazole Metrifonate Oxamniquine Praziquantil

� Egg deposition

Organophosphorus compound with anti-Ch.E Activity � Depolarization Block & paralysis

- Bind DNA - � Egg deposition

� Ca ++ inaflux � Spastic Paralysis Mechanism

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 & protinuria 4- Fever.

1- CNS: - headache - dizziness 2- GIT disturbance 3- Arthritis & Myalgia 4- Fever & Pruritis

S.E:

- pregnancy - Epilepsy.

- pregnancy - pregnancy - Epilepsy

- pregnancy - child < 4y C.I

Chemotherapy

305

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- Mebendazole 2- Albendezole 3- Thiabendezole

(4)Strongyloides: (Thread worm)

1- Praziquantel 2- Niclosamide

(5) Tainia sagineta

1- Praziquantel 2- Atebrine

(6) Tainia Solium

1- Praziquantel 2- Niclosamide

(7) Hymenolepis nana

Chemotherapy

306

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 antibiotics b- 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 vascular insufficiency � � 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