:Lecture 10

Antibiotics &Anti-infective agents

1
:Microbiology
:Type of cells

.Prokaryotes: No Nucleus, No organelles*

.E.g. Bacteria, spirochetes, Chlamydia, ricketssia

.Eukaryotes: Well defined nucleus & membrane bound organelles

.E.g. animal &plant cells, Fungi, Protozoa, metazoan

Viruses: they are extremely small microbes that are essentially fragments of nucleic **
.acid (DNA or RNA) packed in protein shells
.Viruses are seen with electronic microscope only *
.Viruses are not living organisms, they are acellular *

Chlamydia & Ricketssiae species: they are also small prokaryotes but larger than
.mycoplasmas
.They have cell walls*

N.B. Viruses & Ricketssiae: They differ from bacteria that they can not survive outside
. living tissue

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3
: The difference between Gm+ve & Gm-ve bacteria *

* Important Definitions :
Endospores
Some bacteria tend to form spores from vegetative cells
Survival not reproductive (One bacterium gives one spore)
Spores are resistant to chemicals, desiccation, radiation, freezing, and heat.
They germinate again in favorable conditions.

What are the differences between Endotoxin and Exotoxin?

Endotoxins:
Endotoxin (Lipopolysaccharide = LPS)
LPS is part of the gram-negative outer membrane

Exotoxins
Are protein toxins, generally quite toxic and secreted by bacterial cells (some
gram+, some gram-)
Can be modified by chemicals or heat to produce a toxoid that still is
immunogenic but no longer toxic so can be used as a vaccine
Exotoxins may be subclassed as enterotoxins, neurotoxins, or cytotoxins
MCQs
Any microorganism can become pathogenic in such individuals.
the likelihood of a particular infectious pathogen causing disease is a function
of the following variables:
1. The level of host resistance.
2. The aggressiveness of the invading organism, which is known as virulence. Toxins
produced by the pathogens can also increase their virulence.
3. The absolute number of the microbes in some instances (dose) or (inoculum).
Reservoirs :
Environments or hosts that support growth of infectious organisms.
Reservoirs can be water, soil, or animals.

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A carrier:
It is a host that has recovered from an infectious disease but continues to shed the
pathogen.

Vectors
They do not cause infectious diseases but carry pathogens from one host to another.
Mosquitoes are vectors for malaria, yellow fever, West Nile virus, and Dengue fever.
Ticks are vectors for Lyme disease, Rocky Mountain spotted fever, and Q fever.
fleas are vectors for the plague.

Classifications of diseases and infections

*Infections are classified as:
Primary infections: if the initial disease is caused by the invading organism.
Secondary infection: it generally occurs because of a weakened immune system or
because of the use of antimicrobials.
*Infectious diseases can also be referred to by their geographic site of onset
community acquired
hospital acquired infection develop after admission to a health care institution
(nosocomial infection).

Communicable diseases
Communicable infectious diseases refer to those that can be transmitted from host to
host.
 All communicable diseases are infectious, but not all infectious diseases are
communicable;
if an infectious disease is highly communicable it is said to be contagious.
 Communicable infectious diseases can be:
 endemic, which refers to a low level of disease within a select geographic area.
An epidemic refers to an explosive outbreak of a disease within a population.
pandemic indicates a disease that is worldwide.

: Types of bacteria *

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 Spectrum of activity & uses of antibiotics**
Some antibiotics e.g. penicillins & Clindamycin (Ampicillin & Lincomycin) → causes *
disruption of normal flora of intestinal M.O→ pseudomembranous colitis due to
.overgrowth of C. defficile

ttt: 1) Metronidazole {250-500mg x3x10}

Vancomycin →taken orally "only case" for conditions that doesn't respond to )2
.Metronidazole
.Cholestyramine resin may be used to bind bacterial Exotoxin )3

Infection M.O Treatment

Syphilis (chancre)
: Lyme disease
It's a disease that is transmitted
.by bite of infected ticks
infections results in skin *
lesions, headache & fever
followed by
meningoencephalitis &
.arthritis
: Rocky mountain spotted fever
Fever & aches in bones &
.joints
Eye infection in neonate
Adult eye infection
Botulism
Gas gangrene
Diphtheria
Legionnaire's disease
Granuloma,T.B
Adult meningitis (epidemic)
Infant meningitis
Neonatal meningitis
Meningococcal encephalitis
Toxic shock syndrome (TTS)
Treponema palladium Single ttt with penicillin G is )1
curative for 1ry & 2ry syphilis (no
.resistance)
Erythromycin or Doxycycline is )2
spirochetes used to treat pts allergic to penicillin
.G
Borrelia burgdorferi single 200 mg doxycycline, given *
within 72 hours after a tick bite can
.prevent development of the disease
.IV Ceftriaxone for severe cases *
Ricketsia rickettsi Tetracycline
**Typhus is characteristic of
rickettsial disease:
1. Epidemic typhus.
2. Murine (endemic) typhus.
3. Rocky mountain spotted
fever.
Chlamydia trachomatus .AgNO3 Erythromycin
Ps. Aeruginosa or St. aureus Aminoglycosides
Exotoxin of clostridium Polyvalent antitoxin
botulinum
Clostridium perfringens No treatment
cl. wekhii & cl. Noviji
Corynbacterium diphtheria Erythromycin
Legionella pneumophilia
Mycobacterium tuberculosis Rifampicin +INH (isonicotinic
hydrazide)+Ethambutol
Neisseria meningitides, S.
.pneumonia
H. influenza Penicillins
,H. influenza, streptococcus B
E. coli, Herpes simplex,
Lysteria, S. aureus (least
.detected)
Penicillin +sulfoxazole
+Chloramphenicol
St. aureus Penicillin

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Nosocomial infection
.)Hospital acquired(
Vaginal infection
Most common UTI in
.pregnancy
Subacute endocarditis
associated with dental
.problems
Ear infection> 4 years
.Ear infection <4 years
Shingles disease
Athlete's foot (tinea pedis)
Brucellosis & toleramide
Blind conjunctivitis
Plague
:DNA Enzymes
E. coli, pseudomonas, staph,
klebsiella, Candida, proteus,
.serratia
Tricomonas vaginalis (flag.
Protozoa)
E. coli
Streptococcus viridans
Strept. Pneumonia, H.
influenza
E. coli, staph aureus
Herpes zoster
Fungus
Chlamydia trachomatus ,
Strept & Neisseria gonorrhea
Yersinia pestis
Metronidazole (flagyl, amrizole) -
.quinacrine
Any antibiotic
penicillin, Erythromycin*
Amoxicillin prophylactic*
Ceclor, Erythromycin + sulpha
Famciclovir & vidarabin + calamine
oath bath
Tolnaftate, clotrimazole
Streptomycin +tetracycline
Erythromycin
.Streptomycin IM, tetracycline (oral)
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Restriction endonuclease: catalyze site specific cleavage of double strand DNA .1
.molecules

'G AATTC 3 '5

CCTTAA G5' Palindrome'3

N.B. They are used by bacteria to protect themselves against viral infection by
.Methylation at cleavage site

Exonuclease: enzyme that hydrolyze phosphodiester bond from either 3' or 5' .2
.terminus of polynucleotide molecule

DNA ligase: formation of phosphodiester bond between DNA bases, sealing breaks in .3
.strands

.requires energy in form of NAD+ or ATP*

.DNA polymerase: required for DNA replication [synthesis] .4

.e.g. E.coli contains polymerase I, II, III

Helicase: unwind DNA double strands .5

?Topoisomerses: relax supercoiled DNA→ How .6

.By inducing double or single strand breaks into backbone of DNA

.N.B. Topoisomerase I→ acts on single strand

.Topoisomerase II [Gyrase] → acts on double strands

Primase [primer]: use DNA strands as template to create RNA primer for initiation of .7
.DNA replication

:aLactam & other Cell wall antibiotics

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 The cell wall is composed of: peptidoglycan polymer that consists of glycan+ peptide *
.cross linkage
.Cell wall inhibitors require dividing M.O *

:Lactams
:Penicillins Cephalosporins
Amoxicillin* 1st generation 2nd generation 3rd generation 4th generation
Ampicillin*
Dicloxacillin* Cefadroxil Cefaclor Cefdinir Cefipime
Ticarcillin* Cefazolin Cefprozil Cefixim
Piperacillin* Cephalexin Cefuroxime Cefotaxime
Oxacillin* Cefoxitin Ceftriaxone
Methicillin* Ceftazidime
Nafcillin* ‫وكستين عايزين يروحوا‬ Ceftizoxime
Penicillin G* ‫روكسى فحطوا بروزيل‬ Ceftibuten
Penicillin V* ‫للعرق فيه كلور‬
Indanyl Carbenicillin*
Carbapenems Monobactams Others Lactams inhibitor
Etrapenem Aztreonam Bacitracin .Clavulonic acid
Imipenem / cilastatin Vancomycin Sulbactam
Meropenem Daptomycin Tazobactam

: Penicillins . 1
M.O.A:*Bactericidal→ interferes with last step of cell wall synthesis (cross linkage *
./transpeptidation)
.a. penicillin binding proteins (PBPs)→located in the bacterial cytoplasmic membrane
.they are bacterial enzymes involved in the synthesis of cell wall *
.antibiotics attack these enzymes*
.N.B. MRSA→ Methicillin resistant staph. aureus due to alteration in PBPs
.b. Inhibition of transpeptidation reaction→ inhibition of cross linkage
c. Production of autolysins→ autolysins are degenerative enzymes produced by the
bacteria for normal remodeling in the cell wall & in the presence of penicillins this
.action proceeds

:Pharmacokinetics
Penicillins are excreted by kidney (excreted unchanged in urine) by active tubular .1
.excretion →inhibited by probencid while Nafcillin is eliminated by biliary route
Most penicillins are incompletely absorbed after oral administration except .2
.Amoxicillin which is completely absorbed

Anti-bacterial spectrum: penicillins are bactericidal*

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. G+ve: → cell wall is easily penetrated
. G-ve: → envelope around cell wall, however porins permit entrance of penicillins
.Pseud. aeruginosa lacks porins → very resistant *

:Classification of Penicillins**
:Natural penicillins (penicillin G & V) )1
.G+ve cocci→ streptococcus (pneumonia, pyogenes, viridans)
.G-ve cocci→ Neisseria (gonorrhea, meningitides)
.Spirochetes→ Treponema palladium (syphilis)
.Anaerobic→ Clostridium perfringens
.G+ve Bacilli→ Bacillus anthracis & Corynbacterium diphtheria
.Penicillin V→ more acid stable*

Anti-Staphylococcal penicillins (Methicillin, Oxacillin, Nafcillin, Dicloxacillin): )2

[MOND]
.Penicillinase resistant penicillins
.Used # penicillinase producing staphylococci
.MRSA→ by Vancomycin

Extended spectrum: (Amoxicillin, Ampicillin) )3

.The same spectrum of penicillin G with more effect on G-ve bacilli *
.Amoxicillin is the D.O.C of Lysteria monocytogenes (G+ve) *
.Used in combination with Clavulonic acid & Sulbactam respectively *

Anti-pseudomonal penicillins: (Carbenicillin, Piperacillin, Ticarcillin) [ CPT] )4

Pseud. aeruginosa # *
Ticarcillin + Clavulonic acid *
Piperacillin + Tazobactam *

N.B. Penicillins + Aminoglycosides:*Synergistic effect as penicillins inhibit cell wall

.synthesis & A.G. inhibits protein synthesis with enhanced permeability
.Caution: penicillin + A.G not in the same vial as: → (+ve) A.G. + (-ve) penicillin→ ppt*

:Resistance *
. lactamase activity )1
.permeability to the drug (efflux pump) ↓ )2
.Altering PBPs (as MRSA) )3

*:Routes of administration
CPT & their combination→ IV & IM*
.Penicillin V, Amoxicillin & Ampicillin +Clavulonic acid→ oral*
.Procaine penicillin G& benzathine penicillin G→ depot (IV)*
.MOND→ given before food (30-60 mins)*

:Adverse effects*
.Hypersensitivity → most common )1

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.The metabolite penicilloic acid reacts with proteins→ Hapten that causes immune Rx
.Diarrhea→ pseudomembranous colitis )2
.Nephritis→ mainly Methicillin )3
.Neurotoxicity→ epileptic patients at risk )4
.Hematologic toxicities→ ↓ coagulation (CPT) )5
.Cation toxicity: penicillins are administered as Na+ or K+ salt )6

N.B Ticarcillin is available as disodium salt→↑ risk of HTN & also it has antiplatelet
. activity→ bleeding
Although Ticarcillin & Carbenicillin products are available as disodium salt, **
? Ticarcillin is preferred over Carbenicillin in ttt of patients with CHF…Why
. Because dose of Ticarcillin is 1/2 that of Carbenicillin
.Hemolytic anemia (coombs test) )7

N.B. *patients infected with infectious mononucleosis experience rash after Ampicillin
. therapy
. patient with penicillin allergy don't shift to cephalosporin but shift to Erythromycin *
. Cross hypersensitivity between Penicillin & Cephalosporin is 10% *
.Test of penicillins Hypersensitivity: → Penicilloyl- polylysine skin test**

N.B. Although –ve reaction to the test doesn't rule out the possibility of an allergic state,
.it does indicate that anaphylaxis isn't likely to occur upon administration

: Cephalosporins .2
:Anti-bacterial spectrum*
1st generation→ as penicillin G, penicillinase- resist [P/EC/K] = proteus mirabilis, E. *
.coli, Klebsiella pneumonia
2nd generation→ G+ve (H. influenza+ Enterobacter aerogenes + Neisseria + [P/EC/K]. *
.[H/E/N/P/EC/K]
.3rd generation→↓ G+ve, ↑G-ve (Ceftriaxone, Cefotaxime D.O.C for Meningitis) *
.Ceftazidime→ pseudo. aerigonosa
.4th generation→ wide spectrum*

.Uses: as penicillins*
.Ceftriaxone, Cefotaxime →CSF→ Meningitis caused by H. influenza**
.Ceftriaxone is used in renal failure
.Cefazolin→ prior to surgery, penetrates bone**

:Adverse effects*
.hypersensitivity especially with patients sensitive to penicillins )1
.Disulfiram like effects )2

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Carbapenems : [Ertapenem, Meropenem, Imipenem] .3
.Taken I.V & excreted renally*
." Imipenem peptidase enz. Toxic metabolite "nephrotoxic *
In kidney
.Imipenem + Cilastatin (dehydropeptidase inhibitor in kidney)*
.No toxic metabolites result from Imipenem→ used for UTIs
:Anti-bacterial spectrum*
.Imipenem/Cilastatin & Meropenem are the broadest spectrum -lactams
.Used as empiric therapy*
.Active# penicillinase producing G+ve, G-ve, anaerobes & p. aeruginosa *
.Adverse effects:*Imipenem/Cilastatin→ N, V, and diarrhea*
High doses→ seizures. (Not seen with Meropenem).

. 4. Monobactams (Aztreonam):→ the lactam ring is not fused to another ring

.G-ve including p. aeruginosa, enterbactericae, not #G+ve & anaerobes #*
.Alternative to patients sensitive to penicillins & cephalosporins *
.taken IM or IV & excreted renally*

. Lactamase inhibitors: [Clavulonic acid, Sulbactam &Tazobactam] . 5

.Binds with -lactamase enzyme with no antibacterial activity*
In combination with lactamase sensitive penicillins e.g. Amoxicillin+Clavulonic acid. *

: 6. Other antibiotics
.a) Vancomycin: → glycopeptides
: M.O.A: inhibit synthesis of cell wall *
Phospholipids .1
.Prevent transglycosylation step in peptidoglycan polymerization .2
. Taken by IV infusion & excreted renally*
. Uses: # MRSA &MRSE (Methicillin resistant staph. Epidermidis) *
Oral form is limited for ttt of life threatening antibiotic associated colitis due to .1
.clostridium defficile or staphylococci
.Quinopristin/ daflopristin &linezolid for Vancomycin resistant organisms .2
Vancomycin + A.G. (synergism) → ttt of enterococcal endocarditis (E.E) .3
.Vancomycin + Ceftriaxone → Meningitis .4
. Resistance : 1) Plasmid-mediated changes in permeability. 2) ↓ binding to receptor *
Adverse effects: 1) fever *
phlebitis in the infusion site )2
Flushing (red man syndrome) )3
.Ototoxicity & nephrotoxicity when comb. With A.G )4

b) Daptomycin: *used as alternative to Quinopristin/ Daflopristin & linezolid in MRSA

.& VRE (Vancomycin resistant enterococci e.g. E.faecium & faecalis)
.Bactericidal→ binds to cell membrane causing depolarization & rapid cell death *
.Activity limited to G+ve organisms. *Used in right-sided endocarditis *
.Indicated for ttt of complicated skin infections caused by S. aureus *
.Not used with HMG-CoA reductase inhibitor (statins) → Muscle toxicity*

.c) Bacitracin: → polypeptide antibiotic

.Only Topically→ due to nephrotoxicity*

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 B. Inhibitors of Protein Synthesis :
Tetracyclines .1 Glycyclines .2 Aminoglycosides .3 Macrolides .4
Tetracycline Tigecycline Amikacin …..A Azithromycin
Doxycycline Gentamycin …G Clarithromycin
Minocycline Neomycin…..N Erythromycin
Demeclocycline Streptomycin…S Telithromycin
Achromycin V Tobramycin….T
Kanamycin
Paromomycin
Chloramphenicol .5 Lincosamides .6 Quinopristin/ .7 Linezolid .8
Clindamycin daflopristin
.Lincomycin
: Tetracyclines .1
.M.O.A: binds reversibly to 30S ribosomal subunit→ inhibit protein synthesis*

:Pharmacokinetics*
Form chelates with Ca2+ (dairy food) Mg2+, Al2+ & Fe3+→  shouldn't be taken with *
.food or antacids
They are metabolized in liver→ metabolites secreted in bile→ reabsorbed via *
.enterohepatic circulation → excretion by kidney
.So hepatic or renal dysfunction → ↑ half life**
Doxycycline→ preferentially excreted via bile into feaces so can be used in renally **
.compromised patients.// ineffective in UTI

:Duration of action of Tetracyclines*

Doxycycline (20 h)>minocycline (19h)> Demeclocycline & methacycline (16h)>
.oxytetracycline, chlortetracycline & tetracycline (9h)
.Long acting agents→ lower & less frequent doses so↓ S.E *

:Anti-bacterial spectrum: D.O.C in*

.Cholera: → Vibrio cholera (Doxycycline) )1
.Lyme disease: → Borrelia burgdorferi (tick bite) →doxycycline 200mg )2
.Rocky mountain spotted fever→ Ricketssia ricketsii )3
.Chlamydial infections: → Chlamydia Trachomatus (sexually transmitted) )4
.Mycoplasma pneumonia: → also with Macrolides )5

:Resistance*
.Inability of the organism to accumulate the drug by efflux mechanism )1
.Any organism resistant to one tetracycline is resistant to all )2
.Most penicillinase producing staph are resistant to Tetracyclines )3

:Adverse effects*
.Gastric discomfort → taken with food not dairy )1
.Calcified tissue→ discoloration of teeth & staning of growth )2
.Fatal hepatotoxicity & renal damage )3
.Phototoxicity→ severe sunburn )4
.Vestibular problems→ Minocycline & Doxycycline )5
.Pseudomotor cerebri→ ↑ intracranial HTN )6
.Superinfection→ Candida (vagina) )7
.Staph (intestine)
Clostridium defficile (pseud. colitis)

.C.I→ pregnant, breast feeding & children < 8years*

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Glycyclines: Tigecycline .2
.Derivative to Minocycline*
Used in complicated skin & soft tissue infections (as Daptomycin) & intrabdominal *
.infections

.M.O.A: as tetracycline*
Antibacterial spectrum: → MRSA, VRE &-lactamase producing G-ve*
.Not active # proteus, providencia & pseudo. (3p)
.Dose: → IV infusion /12hrs*
:Adverse effects*
.Vestibular problems→ nausea & vomiting )1
.Photosensitivity )2
.Teeth discoloration )3
.C.I→ Pregnancy )4
:Interactions *
.Not with oral contraceptives )1
Warfarin conc. ↑ )2

: 3. Aminoglycosides
.M.O.A: They bind to 30S ribosomal subunit causing misread to the genetic code *

Anti-bacterial spectrum: The bactericidal effect is conc. & time dependant so ↑drug *
.conc. →↑ rate of organism dicing so once daily dosing can be employed
.G-ve bacilli including pseudo. Aeruginosa → (empiric therapy) *
.pseud. aeruginosa→ Tobramycin + Piperacillin/ Ticarcillin *
Enterococci→ streptomycin/ Gentamycin + Vancomycin/  lactam*
.Tularemia→ Gentamycin (pneumonia)*
.Resistance: 1) ↓ drug uptake *
Enzymes synthesis that modifies or inactivates antibiotic → Amikacin is less )2
.susceptible to these enzymes
Administration: All are given parenterally except Neomycin→ topical only because it *
.is severely nephrotoxic
.Excretion: they are excreted renally unchanged by Glomerular filtration *

:N.B Amikacin differs from others that

.Broadest spectrum G-ve bacilli )1
.Least susceptible to bacterial enzymes that inactivate aminoglycosides )2
:Maximum Gentamycin serum level that doesn't cause toxicity**
.For traditional dosing→ 10g/ml. 2) For once daily dosing→ 20g/ml )1

:Adverse effects*
Ototoxicity→ damage to cochlear & vestibular portions of auditory nerve [8 th cranial )1
.nerve]
Nephrotoxicity )2
.Neuromuscular paralysis→ ↓ Ach release from presynaptic nerve ending )3
.Allergic reactions→ contact dermatitis with topically applied Neomycin )4
.C.I: Myasthenia gravis →to reverse block take calcium gluconate or Neostigmine *

N.B. 1. Viomycin→ polypeptide structure

.it shares some properties with streptomycin (i.e. both have anti T.B. activity)*
Q) Put (T) or (F): Viomycin is closely related in structure to streptomycin (F)
.Other polypeptide Abs: Polymyxin B & Colistin .2
.M.O.A: disrupting of m.o cytoplasmic membrane

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 .Spectrum: G-ve organisms
S.E: nephrotoxicity

: Macrolides .4
.M.O.A: binds irreversibly to 50S ribosomal subunit→ inhibit protein synthesis *
Telithromycin→ 1st ketolide (in macrolide resistant G+ve)

.Spectrum: They are bacteriostatic but may be cidal at higher doses *

.Erythromycin: as penicillin G )1
.D.O.C in Chlamydia during pregnancy
.Clarithromycin: as Erythromycin )2
.H. Influenza, H- pylori, Chlamydia, Legionella, Moraxella & ureaplasma (CHULMH) #
.Azithromycin: → respiratory tract infections (H. influenza & Moraxella) )3
.Preferred in urethritis caused by Chlamydia
.Telithromycin: similar to Azithromycin )4
.Neutralizes all resistance mechanisms

.Erythromycin structure: macrocyclic lactone ring + sugar moiety **

.Resistance: 1) presence of Efflux mechanism*

.affinity to 50S ribosomal subunit ↓ )2
.Plasmid mediated erythromycin resistance (Azi& clari) )3
.Telithromycin # resistant strains

.Pharmacokinetics: *They are taken orally*

.Erythromycin & Azithromycin are affected by food*
Erythromycin is destroyed by gastric fluid so to be taken orally either enteric coated *
.tablets or esterified forms are used
Metabolites of Erythromycin & Azithromycin appear in the bile while Clarithromycin *
.appear in the urine
.they can diffuse to the prostatic fluid *
.Erythromycin & Telithromycin→ inhibit cyp 450*

:Adverse effects *
Epigastric distress→ with Erythromycin but Clarithromycin & Azithromycin are )1
.better tolerated
.Ototoxicity → with Erythromycin )2
Cholestatic Jaundice → occurs with the estolate form of Erythromycin due to )3
.hypersensitivity Rx

:C.I*
.Hepatic dysfunction )1
.Telithromycin→ Myasthenia gravis )2

: Chloramphenicol .5
.M.O.A: Binds to 50S ribosomal subunit (as Macrolides)*

.Spectrum: # ricketssia, anaerobes (broad spectrum)…..not active # pseudo. aeruginosa *

Resistance: R factor that encodes for acetyl CoA transferase→ may inactivate *
.Chloramphenicol

.Adverse effects: 1) Anemia & Aplastic anemia*

.Gray baby syndrome→ cyanosis & death )2

.C.I: With Warfarin & phenytoin: → Chloramphenicol ↑ their conc*

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. Clindamycin: → it dissolves in H2O .6
.M.O.A: Binds to 50S ribosomal subunit*

.Spectrum: anaerobes (Bacteroids fragilis) & G+ve *

.Resistance: as Erythromycin (efflux, affinity & erythromycin esterase) *

Adverse effects: fatal pseudomembranous colitis (ttt by Metronidazole & *

.Vancomycin)→ diarrhea

. Quinopristin / Daflopristin : →30/70% . 7

M.O.A: Each component of this combination drug binds to separate site on 50S *
.ribosomal subunit→ Synergism→ bactericidal

.Spectrum: VRE (enterococcus faecium not faecalis) & MRSA *

.Resistance: a) efflux pump*

.b) plasmid-mediated transferase inactivates daflopristin
.c) Ribosomal enzyme interferes with Quinopristin binding

.Injected IV in 5% dextrose (unstable in saline)*

.Adverse effects: 1) Venous irritation *

.Arthralgia & Myalgia )2
Hyperbilirubinemia →↑ total bilirubin due to competing with )3
.antibiotic for excretion

.Interactions: 1) Inhibit cyp450. 2) Interacts with digoxin (as Erythromycin)*

:Linezolid .8
M.O.A: Binds to 50s ribosomal subunit near the interface with 30s subunit → inhibit *
.formation of 70s initiation complex inhibits protein synthesis

.Spectrum: MRSA, VRE (faecalis & faecium) & penicillin resistant streptococci *
Mycobacterium tuberculosis & Lysteria monocytogenes & #*
.Corynbacterium
.No effect on cyp450**

.Adverse effects: 1) Rash*

.Thrombocytopenia if the drug is taken > 2 weeks )2
.GIT, nausea & diarrhea )3

N.B. Among all protein synthesis inhibitors only Aminoglycosides are bactericidal while
. others are bacteriostatic

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 C. Quinolones, Folic Acid Antagonists, & Urinary Tract
:Antiseptics
Fluroquinolones Inhibitors of Folate Inhibitors of Combination U.T Antiseptics
synthesis Folate reduction
)Sulfonamides(
1st generation Nalidixic à silver sulfadiazine* Trimethoprime* Cotrimoxazole* Nitrofurantoin*
: 2nd generation .Sulfadiazine* Pyrimethamine* Methenamine*
Ciprofloxacin Norfloxacin .Sulfamethoxazole*
.Ofloxacin .Sulfasalazine*
3rd generation .Sulfacetamide*
Levofloxacin. Gatfloxacin .Sulfisoxazole*
Sparfloxacin Succinyl-*
: 4th generation .sulfathiazole
Moxifloxacin Trovafloxacin .Mafenide*
: Fluroquinolones .1
M.O.A: They inhibit replication of bacterial DNA by interfering with DNA gyrase *
.(Topoisomerase II) & Topoisomerase IV
.Spectrum: 1) Active # G-ve as pseudo, H. influenza & Moraxella *
.1st → G-ve )2
.2nd → G-ve, G+ve & atypical org. (Mycoplasma pneum & Chlamydia pneum.) )3
.3rd → G-ve, ↑ G+ve & atypical org )4
.4th → G-ve, ↑ G+ve & anaerobes )5

D.O.C → Anthrax )1
Ciprofloxacin .Resp. tract infection→ NOT D.O.C →weak # Strept pneum )2
UTI 4)Gonorrhea 5)GIT infections )3
The most potent Quinolone # pseudomonas aeruginosa )6
Norfloxacin G-ve (pseudo aerug.) # )1
.G+ve UTI & Prostatitis )2
Levofloxacin Gonorrhea 2) Prostatitis (E. Coli) )1
Acute bronchitis 4) RTI (S. pneumonia) )3
Moxifloxacin G+ve 2) Anaerobes ↑ )1
.Weak # pseudo. aeruginosa )3
.Route: All can be taken orally except Trovafloxacin→ taken IV*
N.B. Levofloxacin, Moxifloxacin, Sparfloxacin & Trovafloxacin → long t1/2 with once
.daily dosing
.Resistance: 1) Mutation of DNA gyrase*
.accumulation due to ↓ porins & efflux pump ↓ )2
:Pharmacokinetics *
.Ca2+, Al3+, Zn2+, Fe3+ & Mg2+→ interfere with the absorption of Quinolones )1
N.B Nalidixic acid: ↓ absorption by food or antacid & common S.E is visual
.disturbances
:Adverse Effects*
. GIT→ nausea, vomiting & diarrhea ) 1
. CNS→ headache & dizziness especially with Ciprofloxacin ) 2
. Phototoxicity → so avoid excessive sunlight & apply sunscreens ) 3
. Connective tissue problems→ CI < 18 years (Arthropathy) ) 4
.CI in pregnancy & lactation
. Liver toxicity→ Trovafloxacin ) 5
. Moxifloxacin & Sparfloxacin → (↑ QTC) → CI in arrhythmia ) 6

17
. Ciprofloxacin & Ofloxacin →↑ Theophylline ) 7
. 3rd & 4th →↑ Warfarin, cyclosporine & Caffeine

: Inhibitors of Folate synthesis → Sulfonamides .2

M.O.A: analogues (have structural similarity) of PABA so they compete with PABA *
for the bacterial enzyme dihydropteroate synthetase →  inhibit the synthesis of
.bacterial dihydrofolic acid (↓ DHF)
:Pharmacokinetics*
Orally: all are absorbed except Sulfasalazine which isn't absorbed so used for ttt of )1
.chronic inflammatory bowel disease e.g. Crohn's disease or Ulcerative colitis

Sulfasalazine Intestinal Sulfapyridine + 5 aminosalicylate (antiinflam. effect)

Flora
Creams: silver sulfadiazine or Mafenide acetate → ttt of burn associated sepsis*

.N.B. silver sulfadiazine is preferred because Mafenide produces pain on application

The Sulfa drugs are acetylated in the Liver→ acetylated product which precipitate at **
.neutral or acidic pH→ Crystalluria "Stone formation" which causes Kidney damage
."Unchanged drug & acetylated metabolites "appear in urine **

.Sulfamethoxpyridine: is long acting as it is highly bound to plasma proteins **

.Safest sulfa to allergic patients is Sulfamethizole**

.Spectrum: Active # enterobacteria in the UT & Nocardia *

Sulfadiazine + Pyrimethamine → Toxoplasmosis & chloroquine resistant malaria
*Resistance: 1) Altered dihydropteroate synthetase
.Permeability of the drug ↓ )2
.production of natural PABA ↑ )3

:Adverse effects*
? Crystalluria → may cause nephrotoxicity → How to overcome ) 1
By: Adequate hydration & alkalinization of urine**
Newer agents such as Sulfamethoxazole & Sulfisoxazole are more soluble at Urinary *
.pH than older sulphonamides → No Crystalluria
. Hypersensitivity: such as rash, angiodema & Steven Johnson syndrome ) 2
. Hemolytic anemia: in patients with Glucose-6-phosphate dehydrogenase deficiency ) 3
. Kernicterus: In new born→ sulfa displaces bilirubin → crosses BBB ) 4
Drug potentiation: ↑Tolbutamide (hypoglycemia), ↑ Methotrexate, ↑Warfarin. 6) CI ) 5
(not with Methenamine (condense)) → Newborns <2 months & pregnancy due to
.risk of kernicterus

.Put (T) or (F): Sulfa drugs aren't liable to decompose by heat (T) **

. Inhibitors of Folate reduction → Pyrimethamine & Trimethoprim .3

:M.O.A*
Folic à dihydrofolate Tetrahydrofolic acid purine, thymidine & amino à synt
.reductase

.This mechanism occurs for both human & microorganisms

*.Spectrum: 20- 50 folds more potent than sulfonamides
.Resistance: 1) Alteration of dihydrofolate reductase *
.Over production of enzyme )2
Uses: Pyrimethamine in parasitic infections & Methotrexate in cancer & R.A *

18
Adverse effects: Megaloblastic anemia, Leukopenia & granulocytosis (symptoms of *
.folic acid deficiency) → ttt with Folinic acid

. Cotrimoxazole : [Sulfamethoxazole (1): Trimethoprime (5)] → synergism .4

Spectrum: 1) UTI 2) RTI 3) GIT *
.Lysteria monocytogenes (septicemia & meningitis) )4
.Pneumocystis jiroveci pneumonia (AIDs) )5

Adverse effects: 1) GIT→ nausea & vomiting. 2) Anemia & Leukopenia. *

.3) Dermatologic

: Urinary tract antiseptics .5

:Pathogens that may cause UTI are*
E.coli 2) Proteus mirabilis 3)Staph. saprophyticus )1
.Klebsiella pneumonia )4

.A. Methenamine: Hexamine Hippurate

:M.O.A*
. Methenamine decomposes at acidic Formaldehyde + ammonium ions*
pH of urine (5.5) toxic to bacteria liver metabolism→ urea
Methenamine is formulated with weak acids such as mandelic acid → lower pH of **
.urine to aid decomposition of drug
.Spectrum: # lower UTIs not upper UTIs*
.Not # proteus
Adverse effects:1) GIT distress 2) Hematuria*
Albuminurea 4) Rashes )3

CI: 1) Patients with liver insufficiency due to accumulation of ammonium ions *

.→ CNS toxicity
.Patients with renal insufficiency because mandelic acid may precipitate )2
.With Sulphonamides→ because sulfonamides react with formaldehyde )3

B. Nitrofurantoin : # E.coli
?Less commonly used & limited only to UTIs………why*
Because it has narrow spectrum & is toxic (causes GIT disorders, acute
.pneumonitis & neurologic problems)
:Agents related to Nitrofurantoin
.Nitrofurazone (topically) &2. Furazolidone (local action) .1

. C. Acetohexamide acid [AHA]: adjunct therapy for UTIs

.N.B. Phenazopyridine→ 1.UT anesthetic available only as oral D.F & analgesic
.Causes reddish discoloration of urine .2
?Not used more than 2 days→ WHY .3
Because it would mask pain that might be indication of failure of antimicrobial
.therapy
.Bacteruria: elevated nitrite level in the urine [bacteria count 10 5]*
.Tested by Microstix

19
:ttt of UTIs by large single doses of drugs*
Amoxicillin: 3g .1
Fosfomycin: 3g .2

:Pregnancy & Antibiotics **

Penicillins: All cross placental barrier but none has been shown to be *
.teratogenic
? Tetracyclines: CI……….Why *
.Discoloration & hypoplasia of neonatal teeth & hepatotoxicity to mother
Aminoglycosides: cross placental barrier & may lead to Ototoxicity & *
.nephrotoxicity of newborn
? Chloramphenicol: "Grey baby syndrome"→ why *
Neonates have a low capacity to glucuronylate the antibiotic & have decreased
ability to excrete the drug which accumulates→ C.V collapse, depressed
.breathing, cyanosis & death
? Fluroquinolones: CI pregnancy, lactation & children < 18 years why *
Because it causes connective tissue problems → articular cartilage erosion
.""Arthropathy
? Sulfonamides: CI pregnancy, newborns & infants < 2 months why *
Sulfa drugs displace bilirubin from binding sites on serum albumin → free
.bilirubin→ pass into CNS BBB of baby isn't fully developed → Kernicterus
Trimethoprim: it produces the effects of Folic acid deficiency → Megaloblastic *
.anemia, leukopenia & granulocytopenia so CI in pregnancy

.N.B ttt of drug induced neonatal Jaundice→ Phenobarbital

:Important extra notes

:Agents active against Helicobacter pylori *
Clarithromycin. 2. Tetracycline .1
.Metronidazole 4. Bismuth subsalicylate .3
The best product for ttt of Otitis media: → H. influenza & S. pneumonia are *
major causes of Otitis media & sinusitis
Trimethoprime/ Sulfamethoxazole .1
.Amoxicillin or Ampicillin .2

3rd generation cephalosporins are more effective in ttt CNS infections such as *
.meningitis than 1st or 2nd generation e.g. Ceftriaxone & Cefotaxime

Phthalylsulfathiazole: is indicated for decreasing intestinal bacterial *

?flora…..Why
It is taken in large doses prior to bowel surgery & used for ttt of certain
.intestinal infections
M.O.A: It's hydrolyzed in large intestine to yield free sulfathiazole which is
.slightly absorbed from GIT

20
:D. Antimycobacterial Drugs

T.B Leprosy
:1st line 2nd line Dapson+ Rifampin+ Clofazimin
Ethambutol Aminoglycosides
Pyrazinamide Fluroquinolones
Rifamycin Macrolides
Isoniazide Cycloserine
Aminosalicylic acid
Capreomycin
Ethionamide

.months therapy 6*
.months→ Isoniazide, Rifampin, Pyrazinamide & Ethambutol 2*
months→ INH + Rifampin 40*
Direct observed therapy (DOT) → system applied to ↓ resistance & improve *
.recovery
The purpose of combination drug ttt in T.B: (takes 6-24 months)**
.Delay emergence of drug resistance .1
.tuberculostatic effects of the drug e.g. Streptomycin & Isoniazide ↑ .2
:Q) Put (T) or (F)
.Drug combination for T.B reduces the duration of therapy (F)

:1st Line treatment

Isoniazide "INH": → it is the hydrazide of isonicotinic acid (synthetic ) 1
.analog of pyridoxine)
M.O.A: Inhibits bacterial cell wall synthesis by inhibiting mycolic acid synthesis
.(by inhibiting InhA & KasA which are important in mycolic acid synthesis)
.INH is deactivated by bacterial Kat G*

Resistance: 1) Mutation in Kat G

.Overexpression of InhA )2

Pharmacokinetics: Affected by food especially Carbohydrates & Al3+ containing

.antacids

.Adverse effects: 1) Peripheral neuritis→ ttt with Vit B6 (pyridoxine)

Hepatotoxicity→ most severe S.E.is due to conversion by )2
.phase II reaction into more toxic metabolite
effect of Phenytoin (inhibit metabolism) ↑ )3
. Nystagmus & Ataxia
:A Patient who is slow acetylator of Isoniazide is characterized by
.Slow metabolism but normal therapeutic response .1
More likely to develop peripheral neuropathy but respond well to ttt with Vit. .2
.B6
So metabolism is in liver & metabolic products & some unchanged drug are
.excreted by kidney
.Metabolites: acetylated form + isonicotinic acid

21
 .Rifamycins: → Rifampin, Rifabutin & Rifapentin )2

:A) Rifampin
.M.O.A: inhibit RNA polymerase  inhibit mRNA synthesis*
.Spectrum: #M.TB, M. kanasii, G+ve, G-ve*
.Used in prophylaxis of meningitis caused by H. influenza
.Most active anti leprosy agent
.Resistance: 1) mutation in RNA polymerase*
.permeability ↓ )2
.Warning: 1) may stain urine & feaces red color**
.Tears may permanently stain soft contact lenses orange-red )2
.Adverse effects: 1) nausea & vomiting*
.Liver dysfunction with elderly & alcoholics )2
.May cause influenza like syndrome "rare )3
.Rash so monitor CBC )4
Drug interactions: "Enzyme inducer"→ ↑ metabolism of oral contraceptives, oral anticoagulants, *
.prednisone, propranolol, Digoxin, ketoconazole, sulfonylurea, Quinidine & Clofibrate
:B) Rifabutin :C) Rifapentin
D.O.C In the ttt of T.B in which patient is * Longer t1/2 than Rifampin & Rifabutin
.infected with HIV .months→ twice weekly 2*
S.E: As Rifampin + hyperpigmentation of .months→ once weekly 4*
.skin+ Neutropenia .never used alone (used in combination to avoid resistance) *

: Pyrazinamide ) 3
." Pyrazinamide bacterial pyrazinamidase Pyrazinoic acid "active form*

hydrolysis
.Some resistant strains lack pyrazinamidase *
.active # tubercle bacilli*
.Both Pyrazinamide & Ethambutol→ cause urate retention→ exacerbate gout*

: Ethambutol ) 4
.Active # M. tuberculosis & M. kanasii *
.M.O.A: It inhibits arabinosyl transferase enzyme  inhibits cell wall synthesis*
Adverse effects: 1) Optic neuritis which results in diminished visual acuity & *
.loss of ability to differentiate between green & red
.Gouty attacks )2

:2nd Line treatment

:Streptomycin .1 1st antibiotic to treat T.B )1
.Streptomycin resistant strains→ Amikacin & Kanamycin )2
Capreomycin .2 .Preserved for multi drug resistant strains
)Parenterally( .May cause Ototoxicity & nephrotoxicity
Cycloserine )3 .Causes CNS disturbances & peripheral neuritis → pyridoxine
:Ethionamide )4 .structural analog of INH & inhibits Acetylation of INH*
.Peripheral neuritis & optic neuritis→ pyridoxine *
Fluroquinolones )5 .Moxifloxacin & Levofloxacin

22
 :Macrolides )6 .Azithromycin & Clarithromycin → pts with HIV

:E. Antifungal Drugs

ttt of Subcutaneous & Systemic Mycosis ttt of Cutaneous Mycoses
.Fluconazole .1 .Terconazole .1
.Ketoconazole .2 .Econazole .2
.Voriconazole .3 .Butoconazole .3
.Itraconazole .4 .Clotrimazole .4
Posaconazole .5 .Miconazole .5
.Micofungin .6 Griseofulvin .6
.Anidulafungin .7 .Nystatin .7
Caspofungin .8 .Terbinafine .8
Flucytosin .9
Amphotercin B .10

:A. Drugs for subcutaneous & Systemic Mycosis

: Amphotercin B .1
.D.O.C in ttt of life threatening systemic Mycoses *
.Can be used in combination with Flucytosin to ↓ conc. of Amphotercin B*
M.O.A: binds with ergosterol in fungal cell membrane→ forms pores→ loss of *
.K+ & leakage of electrolytes→ fungal cell death
Spectrum: Candida Albicans, Cryptococcus neoformans, coccidioides immitis, *
.Blastomyces dermatitidis & Histoplasma capsulatum
.Also used in ttt of protozoal infections, Leshmeniasis *
:Pharmacokinetics*
.By slow IV infusion )1
:Formulated as lipid formulations )2
Amphotercin B + Liposomes→ liposomal Amphotercin B
.Adv: ↓ Nephrotoxicity & infusion toxicity
.E.g. AmBiSome, Abelcet & Amphotec
When renal dysfunction occurs due to Amphotercin B→ dose reduction to )3
.50%
.Resistance: ↓ ergosterol content of the fungal membrane (rare) *
:Adverse effects *
Fever & Chills→ after 1-3 hours of administration→ use antipyretic or )1
.corticosteroids
+
Renal impairment: ↓ Cr cl, ↓K+ & Mg2 )2
. IV infusion of saline before & after drug→ ↓ renal impairment
.Hypotension & Hypokalemia: CI with digitalis  K+ supplement is required )3
Anemia: ↓ erythrocytes production (exacerbated in AIDs pts taking
.Zidovudine)
.Neurologic effects: after intrathecal injection )5
.Thrombophlebitis: So add Heparin to the infusion fluid )6

: Flucytosin (5-FC) .2
M.O.A: Synthetic pyrimidine forms a false nucleotide that inhibits thymidylate *
.synthesis → Thymidylic acid → ↓ DNA synthesis

23
 Spectrum:1)In combination with Amphotercin B→ Cryptococcus reformans *
.& Candida Albicans→ Meningitis
.In combination with Itraconazole→ Chromoblastomycosis )2
.Pharmacokinetics: Oral route. Penetrates CSF*
Adverse effects: 1) Neutropenia 2)Thrombocytopenia*
.Bone marrow depression 4) GIT disturbances )3
:Azoles .3
Ketoconazole Fluconazole ItraconazoleVoriconazol Posaconazole
e
:M.O.A . Lanosterol demethylation Ergosterol: they block cyp450 enzyme imp
Cyp450 for demethylation of Lanosterol
Routes Oral Oral, IV Oral Oral ,IV
CSF No Yes No ----- ---------
penetration
Renal No Yes No ------ -------
excretion
Spectrum Narrow Expanded Expanded ------ --------
Pregnancy All are teratogenic so CI in the pregnancy
:S.E .Nausea, vomiting, rashes & Hepatitis [rare]
Ketoconazole only: inhibits human gonadal & adrenal steroid synthesis leading to ↓
testosterone & cortisol production→ Gynecomastia, Libido, impotence & menstrual
.irregularities
DI All are inhibitors of cyp450 enzyme of human with ketoconazole being the most
.potent. e.g. ↑ toxicity of some drugs with Theophylline
Notes it requires * D.O.C for * * may cause * administered *
gastric acid for 1) Itraconazole transient .with meals
absorption so Cryptococc + 5fc→ttt of visual ttt of oroph. *
any drug ↓ us Chromoblas disturbance candida→ once
gastric à→↓ .neoformans .tomycosis .daily
.absorption )2 D.O.C for * prophylaxis→ 3 *
Ketoconazole &* candidemia aspragillosis .times daily
amphotercin B )3 , sporotri-
shouldn't be used Coccidioido chosis &
?together….why .mycosis paracoccidi
Because used ** .oidomycosis
ketoconazole↓ prophylactic
ergosterol in ally to ↓
fungal memb.→↓ fungal
fungicidal action infections in
of Amphotercin bone
B marrow
transplants
:N.B: Drug interactions with ketoconazole
.Antacids, H2 receptor blockers, PPIs→↓ acid→↓ absorption .1
.Food→ ↓ absorption .2
Amphotercin B .3
Ketoconazole inhibits metabolism of Cisapride, astemizole & terfinadine →↑ plasma .4
.level→ Arrhythmia {Torsade de points}

:Echinocandins .4
Caspofungin .1 M.O.A: inhibit  (1,3)D- glycan→inhibit cell wall *
)not orally( synthesis

24
 .spectrum: limited to Aspragellus & candida*
SE: Rash, nausea, vomiting & flushing (due to *
.histamine release)
.N.B. Shouldn't be administered with Cyclosporine
Micofungin & Anidulafungin .2 .not active orally but IV infusion*
.Histamine mediated S.E*
:B. Drugs for Cutaneous Mycoses
."Superficial skin infections are called dermatophytes e.g. tinea "ring worm **

Terbinafine .1 Griseofulvin .2
:M.O.A Inhibits squalene epoxidase enzyme Inhibition of mitosis of fungal
→necessary for synthesis of ergosterol "cell "Fungistatic
. inhibit ergosterol formation
also accumulation of squalene→ cell *
"death "fungicidal
Spectrum D.O.C for ttt of dermatophytes As Terbinafine but
especially "Onchomycosis [fungal Terbinafine replaced it
infection of nails] because it is more effective,
ttt duration: 3 months .also for tinea capitis
ttt duration:6-12 months
Route Orally active with bioavailability 40 % Oral & absorption ↑ by high
due to 1st pass effect fat meal
:S.E *.Nausea, diarrhea, rash, hepatitis (rare) exacerbate intermittent *
taste & visual disturbances* .porphyria
Not taken with alcohol→↑ *
toxicity
D.I .Rifampin→↓blood level of Terbinafine It is Enzyme inducer**
Cimetidine→↑ blood level of
.Terbinafine
Nystatin :→polyene antibiotic with same characteristics of Amphotercin B . 3
oral wash for oral candidiasis*
: Miconazole, clotrimazole, Terconazole & Butoconazole . 4
.topically used & not used parenterally due to severe toxicity*
.S.E: contact dermatitis, vulvular irritation
D.I: Miconazole inhibit warfarin metabolism→ ↑ bleeding even topically used

25
 :F. Anti-protozoal Drugs
: Amebiasis: *Life cycle of Entamoeba histolytica . 1

:Clinical syndrome : Drugs

:Asymptomatic cyst carriers .1 Iodoquinol or Paromycin or Diloxanide furoate
Diarrhea/Dysentery .2 Metronidazole + Iodoquinol or Paromycin or
""Extraintestinal .Diloxanide furoate
:Amebic Liver abscess .3 .Chloroquine + Metronidazole or Emetine

:Drug :Comment
Metronidazole .1 .M.O.A: destruction of helical structure of DNA *
"mixed ameobicide" .Other uses: 1) ttt of Giardiasis (D.O.C) *
®)flagyl( Trichomonas vaginalis )2
Anaerobic→ Bacteroids species "C. defficile/ )3
."pseudomonas colitis
"S.E: 1. Epigastric distress, nausea & vomiting "most common
.Unpleasant metallic taste .2
."CNS dizziness & numbness "rare .3
.If taken with alcohol→ disulfiram-like effects .4
.Urine turn red brown color .5
Iodoquinol .2 .S.E: 1. Rash
High dose long term use: peripheral neuropathy & optic .2
.neuritis
.May interfere with the results of thyroid tests .3
Diloxanide furoate .3 ."S.E: Mild "Dry mouth, flatulence & Urticaria
.C.I: Pregnancy & children < 2 years
Paromomycin .4 .M.O.A: Aminoglycoside antibiotic→ protein synthesis inhibitor
S.E: Taken orally with insignificant absorption so S.E include only
.GIT distress & diarrhea
Emetine & .5 M.O.A: They are alkaloids obtained from Ipecac→ They kill amebae

26
 Dehydroemetine .by inhibiting protein synthesis
.S.E: 1. Taken I.M→ pain at injection site
.Toxicity: CVS [arrhythmia & CHF] .2
.Neuromuscular weakness

:Malaria .2
:Life cycle of the malaria parasite *
An infected mosquito injects Sporozoites→ Sporozoites migrate to the liver, where they
form merozoites→ Merozoites are released & invade red blood cells→ in the red blood
cell, the merozoite becomes a trophozoite → Trophozoite use Hb as nutrient→
Trophozoites multiply producing new merozoites→ merozoites infect other RBCs or
become gametocytes→ female mosquito picks up gametocyte from an infected human→
.sexual cycle occur in mosquito & form sporozoite

.Characteristics of the disease: 1.persistant high fever*

.Orthostatic hypotension .2
Massive erythrocytosis [abnormal elevation of RBCs] .3
.ttt: 1) Tissue schizonticide→ drug is effective against exoerythrocytic form
. Blood schizonticide→ drug is effective against erythrocytic form ) 2

All plasmodium species except Chloroquine [4- aminoquinoline]

chloroquine resistant P. Falciparum
Chloroquine resistant
P. Falciparum
:Prevention of relapses
P. vivax & P. ovale only
Prevention of malaria
Pregnancy
Quinine +Pyrimethamine/ Sulfadoxine or Doxycycline or
Clindamycin
Alternate: Mefloquine
Primaquine
.Chloroquine sensitive geographic areas: Chloroquine *
.Chloroquine resistant geographic areas: Mefloquine *
Chloroquine or Mefloquine

Drug Comment
A. Tissue S.E: 1. Drug induced hemolytic anemia in pts with G-6-phosphate
:schizonticide .dehydrogenase deficiency
Primaquine .Abdominal discomfort especially if taken with Chloroquine .2
.C.I: in patients with Rheumatoid arthritis & Lupus erythromatoses
B. Blood M.O.A: Hb digestion by the*
:schizonticide "Parasite Amino acids "food for the parasite
:Chloroquine .1 " Heme "toxic to the parasite
Chloroquine (-) polymerization by the parasite
" Hemozoin "untoxic
N.B: chloroquine has anti-inflammatory action so may be used in Rheumatoid
.arthritis & lupus erythematosues
.S.E:1) bec. it concentrates in liver so use with caution in Hepatic disease
.Used with caution in patients with GIT, neurologic or blood disorder )2
Ophthalmologic examination should be routinely performed due to visual )3
.disturbances
.C.I: in patients with psoriasis or porphyria
.DI: with Gold or Phenylbutazone→ aggravation of dermatitis
Mefloquine .2 .If Mefloquine is taken with quinine or quinidine→ cardiac arrest*
If Mefloquine is taken with quinine or chloroquine→↑ risk of convulsions*

27
Quinine & .3 ." S.E: 1. Cinchonism "tinnitus, vertigo & nausea
:Quinidine C.I: in patients with Glucose-6-phosphate dehydrogenase deficiency & ttt is
.stopped if +Coombs test for hemolytic anemia occurs
DI: 1) with neuromuscular blockers→ potentiation
with Digoxin→ ↑digoxin level so ↓ dose by 1/2 )2
.With Al antacids→ related quinine absorption )3
Fansidar .4 .It's also active against T. gonadii*
.S.E: May cause fatal hypersensitivity reactions
Artemsinin .5 For ttt of multidrug resistant P. Falciparum
‫الطب الصينى‬
Pyrimethamine.6 N.B: If it causes megaloblastic anemia→ ttt with Leucoverin (protects against
.folate deficiency)

. Toxoplasmosis: cause Toxoplasma gonadii . 3

.ttt: Pyrimethamine / Sulfadiazine & Fansidar
N.B: At first appearance of rash Pyrimethamine should be discontinued because it may
.cause severe hypersensitivity → Fatal

" Leshmaniasis: "transmitted by infected sandflies .4

ttt: Na stibogluconate: taken IV
.S.E: pain at injection site & cardiac arrhythmia
.Pentamide+ Amphotercin B as backup*
.Allopurinol: may be effective*

: Trypanosomiasis .5
:American :African
Caused by .Caused by Trypanosoma brucei
.Trypanosoma cruzi "Transmitted by bite of Tsetse fly "sleeping sickness
.Called Chagas disease* .T. brucei rhodesiense* .T. brucei gambiense*
transmitted by insect * .Early invasion of CNS* .Slow to enter the CNS*
feces contaminating eye Fatal if not treated*
.or skin lesions
Causes *
cardiomyopathy
ttt Nitrofurtimox ttt Melarsoprol ttt Pentamidine Isethionate Surdmin
Suppressive* Unlike Pentamidine it * M.O.A: inhibition of DNA, * Paresthesia of *
M.O.A: it undergoes * penetrates CSF so used RNA, Phospholipids& protein .hands & feet
reduction→ generates for T.brucei rhodesiense synthesis of Pneumocystis Edema of *
oxygen radicals→ toxic & meningoencephalitis .crainii (PCP) .eyelid
.to T.cruzi caused by T.brucei S.E: 1. It is taken either by * Nausea & *
S.E:1) immediate * .gambiense aerosol, I.M or I.V .vomiting of GIT
hypersensitivity Rx e.g. S.E: 1) CNS toxicity e.g. * a)Aerosol: cough & :Albuminurea*
.anaphylaxis .encephalopathy .bronchospasm If renal casts or
Delayed )2 After injection: )2 b) Parentral: severe Hematuria
hypersensitivity Rx e.g. hypersensitivity Rx, fever .hypotension .occur→cease ttt
.dermatitis .& severe vomiting .Nephrotoxicity .2 Shock & loss of*
Severe GIT problems )3 C.I: 1) pts with influenza Toxic to  cells of the .3 consciousness
.that may cause wt loss Pts with Glucose- )2 pancreas→ may cause due to

28
Peripheral )4 6-phosphate .reversible IDDM .hypersensitivity
.neuropathy (common) .dehydrogenase deficiency

:G. Antihelmentic Drugs

Nematodes Trematodes Cestodes
Mebendazole Praziquantel Albendazole
Thiobendazole Niclosamide
Ivermectine
Pyrantel pamoate
Diethyl carbamazine

: I. Drugs for Nematodes

Mebendazole Thiobendazole Pyrantel Ivermectine Diethyl-
pamoate carbamazine
M.O.A Interferes with parasites Depolarizing Cl- influx→ ↑ Immobilize the
microtubule &↓ glucose uptake NMB→ hyperpolarizatio parasite &
paralysis of n render them
worm→ Worm → susceptible to
expelled with .paralysis host defense
feces
Spectrum :Whip worm.1 :Thread worm .1 In combination :D.O.C in :Filariasis*
Trichuris Strongyloides with Onchocerciasis .1 wucheria (
trichuria .stercolaris Mebendazole # .)River blindness( bancrofti &
:Pin worm .2 : Trichirosis .2 round, pin & )Brugia Malayi
Enterobius Trichirella hook worms Thread worm .2 in combination
vermicularis .spiralis Strongyloides ( with
:Hook worm .3 .)stercoralis Albendazole
Nectar
Americans
&Anclystoma
.duodenale
:Round worm .4
Ascaris
.lumbercoids
S.E N, V & .1 Mazotti- like Fever, malaise
.Anorexia reactions rash &
Stephen .2 (headache, →Arthralgia
Johnson dizziness, 
.syndrome somnolence & antihistamines
Many .3 hypotension) & steroids are
.fatalities given to ↓
.symptoms
C.I In pregnancy:→ Meningitis: .1
embryotoxic & .can cross BBB
teratogenic Pregnancy .2
Notes Not absorbed Absorbed orally

29
 orally except
with fat meals

II. Drugs for Trematodes : → Praziquantel

.M.O.A: ↑ Ca2+ influx→ contraction→ paralysis of worm*

.Spectrum: 1) Schistosomasis*
.Lung fluke→ paragonimiasis )2
.Liver fluke→ clonorchiasis )3
.Cestodes as cysticercosis )4

S.E: 1) GIT disorders 2) Dizziness *

Malaise 4) Anorexia )3

.C.I: 1) Pregnancy & lactation*

.Ocular cysticercosis (worm death cause destruction of eye) )2

III. Drugs for Cestodes : → Cestodes = tape worm infection

Niclosamide Albendazole
:M.O.A Inhibits conversion of ADP→ ATP As Mebendazole
Spectrum .all Cestodes* Cysticercosis caused by taenia .1
active # segments* solium
not # ova* Hydatid disease→ echinococcus .2
granulosis→ 3 months
C.I With alcohol: 1 day of Niclosamide .In pregnancy & Children<2 years
Notes A laxative is given prior to oral Nematodal infection→1-3 days
administration to purge the bowel of therapy
dead segments & so preclude
digestion & liberation of the ova
.which may lead to cystericercosis

N.B: Albendazole is the drug of choice for mixed intestinal worm infection (effective
against a broader spectrum than Mebendazole). It is better absorbed than Mebendazole,
and consequently is more useful in treating tissue forms of infections.

30
 :H. Anti- Viral Drugs
Respiratory tract Hepatic virus Herpes & Cytomegalovirus
Amantadine Lamivudine Gancyclovir Cidofovir
Rimantadine Interferon Acyclovir Foscarnet
Zanamivir Telbivudine Famciclovir Fomivirsen
Oseltamivir Adefovir Valacyclovir Vidarabin
Ribavirin Entacavir Penciclovir
‫واحد اسمه الميفودين بيدخل فى شئون‬ Valganciclovir
‫الناس و كمان بيدعى كأنو أديفوفير‬
‫فواحد قاله انت كافير‬

:I. Respiratory tract infections

:Neuraminidase inhibitors.1 :Inhibitors of viral uncoating .2 Ribavirin

Oseltamivir Zanamivir Amantadine Rimantadine

Notes Prophylaxis & ttt of influenza * Prevention & ttt # influenza A * DNA &RNA #*
.A & B .only .viruses
Prevent infection, however if * Amantadine is effective # some * RSV # *
given 24-48 hrs after .cases of Parkinson's disease (respiratory
infection→↓ duration & Resistance: change in one à à of * synctial virus) in
.intensity of symptoms .M2 protein (occurs in 50% of pts) .infants & young
Hepatitis C in #*
combination with
.interferon  b
:M.O.A Neuraminidase→ inserted into* Block matrix protein M2 → blocks Inhibits viral
.host cell memb.→ new virus H+ channels→ no fusion of the mRNA capping &
Oseltamivir & Zanamivir * viral membrane with the cell block RNA
(analogs of sialic acid) → membrane→ no endosome→ no .polymerase
.inhibit neuraminidase uncoating
Pharmaco- Oseltamivir (prodrug) → * .Amantadine → cross BBB* Oral & IV*
:kinetics .orally Rimantadine → doesn't cross * Inhalation in RSV*
Zanamivir→ inhaled or * BBB .(aerosol)
.intranasal Absorption ↑ with*
.fatty meals
Pregnancy Can be used in pregnancy * Teratogenic Teratogenic*
.(category C)
:S.E Oseltamivir: →GIT * Both causes GIT intolerance* Transient anemia *
.disturbance & nausea Amantadine→ CNS S.E (ataxia, * .&↑↑ bilirubin
Zanamivir: → not given to * .insomnia & dizziness)
asthmatic & COPD Rimantadine→ fewer CNS S.E as*
it doesn't cross BBB

31
 .N.B: Amantadine is tricyclic amine
.Dose: 200mg for 2-3 days before & 6-7 days after influenza A infections
.Amantadine is active against influenza A not B

:II. Anti-Virals for Hepatic viral infections

.Chronic HBV (hepatitis B virus): Interferon - [INF-] + Lamivudine*

& Chronic HCV (hepatitis C virus): Interferon - [INF-] + Ribavirin (Taken IV or orally*
.)S.E: transient anemia with elevated bilirubin
.N.B: Patients with AIDS &hepatitis B are weak responders to interferon
:A. Interferon M.O.A: Induction of host cell enzymes→ degradation of viral mRNA & *
.tRNA →  inhibit RNA translation
Administration: it is glycoprotein so taken IV, S.C or intralesionally (not *
.orally)
Interferon+ PEG→ pegylated form→ prolongs duration (t1/2) → once *
.weekly dosing
:Interferon  b is approved for*
.Hepatitis B&C )1
Condylomata acuminata)2
Cancers as hairy cell leukemia & Kaposi's sarcoma)3
:B. Lamivudine (3TC) It is a cytosine analogue that is active against HBV DNA polymerase &HIV *
.reverse transcriptase
orally→ t1/2 (9 hours)*
must be phosphorylated to triphosphate form *
:C. Adefovir dipivoxil *Adefovir dipivoxil is metabolized to Adefovir diphosphate
*A nucleotide analogue of deoxyadenosine monophosphate
*Acts as an alternative substrate for viral DNA polymerase resulting in DNA
chain termination and prevention of viral DNA synthesis.
.Once daily dosing*
.Discontinuation leads to exacerbation of hepatitis in 25% of pts *
D. Entecavir *Entecavir is a guanosine analogue
triphosphate *Inhibits hepatitis B polymerase, preventing viral DNA synthesis.
*Once daily.
*# Lamivudine resistant HBV
*Discontinuation leads to ↑↑ hepatitis
E. Telbivudine *A thymidine analogue
triphosphate *Inhibits hepatitis B polymerase, preventing viral DNA synthesis.
*Once daily

32
 :III. Herpes Virus Infections
Herpes simplex virus .1
:HSV-1
:HSV-2
:Varicella zoster virus (VZV) .2
:Cytomegalo virus (CMV) .3
Episten barr virus (EB virus) .4
:Lysteria monocytogens"
Cold sores: watery blisters on skin & mucous membranes
especially lips
Genital warts
. Shingles: infection at dorsal root ganglia
.Characterized by: 1. Vesicular eruption
Neurologic pain in the .2
.dermatome of the affected root ganglia
Causes retinitis in immunocompromised patients
A herpes virus which is the etiology agent of mononucleosis
(increase number of Monocytes)

:A. Guanine analogue

*Mode of action
Following phosphorylation by viral and cellular enzymes, guanine analogues inhibit viral DNA polymerase
and DNA synthesis.
*Indications
Treatment and prevention of herpes simplex infections (acyclovir, famciclovir, valaciclovir)
Shingles (aciclovir, famciclovir, valaciclovir)
Treatment and prevention of CMV disease (ganciclovir, valganciclovir)
*Precautions: Serious adverse reactions to individual drug or metabolite—contraindicated.
Renal: Dosage adjustment required in renal impairment.
*Counseling: may make you feel dizzy or confused. Don’t drive or operate machinery.
:Acyclovir .1 .HSV1, HSV2 , VZV & EB#*
*Taken: oral, IV & .Most common use for genital infections *
topical *D.O.C for HSV encephalitis : IV 10 mg/kg every 8 hours.
SE: oral→ nausea, vomiting&headache
Topical→ local irritation
:Valacyclovir.2 Volyl ester of acyclovir→ valacyclovir→ >oral bioavailability than *
.acyclovir
doses of valacyclovir→ Thrombotic thrombocytopenia purpura in ↑↑*
pts with AIDS
:Ganciclovir.3 .only#CMV induced retinitis in immunocompromised pts *
.IV only* 8-20x > effective than acyclovir#CMV*
SE:1) Neutropenia→↑ when combined with zidovudine, azathioprine*
.mycophenolate → black box warning &
.Photosensetivity & fever (common))2

33
 .carcinogenic, teratogenic & embryotoxic)3
Valgancyclovir .4 Higher oral bioavailability than ganciclovir
:Penciclovir .5 .HSV1 &2 &VZV#*
Only topical *t1/2>20-30x acyclovir*
N.B: Famciclovir: is a prodrug for the active agent penciclovir which can
.be used orally #VZV
.S.E: Adenocarcinoma & testicular toxicity

:B. Others
:Cidofovir .1 CMV induced retinitis in AIDs patients#*
IV & Intravitreal (eye SE: Nephrotoxic Co-adminstered with probencid to ↓ nerotoxicity *
vitrious humor)
:Foscarnet .2 .Reversibly inhibit RNA polymerase *
IV (not oral) .CMV induced retinitis & acyclovir resistant HSV & VZV #*
.S.E: 1) Nephrotoxicity, anemia, nausea & fever
It is pyrophosphate → Chelation with divalent ions )2
.→hypocalcemia & hypomagnesemia
.Arrhythmia & seizures )3
Vidarabine .3 Available only as ophthalmic ointment for ttt of herpetic keratitis (=keratitis *
:)Ara-A( formed by HSV), It has been replaced by acyclovir which is more effective &
.safer
.Slow IV infusion for ttt of H. simplex encephalitis *
:Fomiversin .4 .CMV induced retinitis →used if other therapies failed #*
Intravitreal .S.E: Iritis, vitritis & changes in vision
:Trifluridine .5 D.O.C in HSV keratoconjunctivitis
Eye solution
:Idoxuridine .6 .M.O.A: It is antimetabolite which inhibits replication of DNA *
D.O.C for H. simplex infection of eyelids & conjunctiva which may cause *
.blindness

34
 .IV. HIV Infections: AIDS
.HIV: it is an RNA virus*

RNA rev. DNA Viral precursor polyprot. protease comp. polyprot. assembly mature vurion

.transcriptase enz

.HIV targets T- helper lymphocytes*

N.B: T- helper lymphocytes have a protein called cluster of differentiation 4 [CD-4]
.which helps recognize & bind antigens→ ELISA test
Treatment: 1)Drugs must be used in combination (highly active antiretroviral therapy) *
.Therapy must be continued for lifelong because they are virastatic )2
:When to start treatment
.Treatment should only be undertaken by specialists in HIV medicine
Symptomatic HIV infection
.Begin antiretroviral treatment
Long term benefit from starting antiretrovirals during the first 2 weeks of treatment for an
.opportunistic infection (except TB)

Asymptomatic HIV infection

*The decision to treat is influenced by the short term risk of developing AIDS and potential
benefits and disadvantages of treatment at various CD4 cell counts and HIV RNA levels.
*Treat people with a CD4 cell count <200/microlitre; treatment is recommended for those
whose CD4 cell count is 200–350/microlitre.
*If the CD4 cell count is >350/microlitre the risk of disease progression is highest if the viral
load is >100 000 copies/mL. Depending on the situation either offer treatment or defer it and
closely monitor the person’s CD4 cell count, HIV RNA and clinical state.
*Treat pregnant women and people with HIV-associated nephropathy or hepatitis B infection
requiring treatment.
*Different criteria are used to guide treatment of children.
Monitoring
Increases in CD4 cell counts and reduction in plasma viral load correlate with treatment
efficacy, although CD4 cell count is sometimes unreliable, eg in children <5 years. CD4 cell
count is an indication of immunodeficiency while viral load indicates response to treatment.
In general, viral load, CD4 cell count and percentage are measured 2–8 weeks after starting
treatment and then every 3–4 months (viral load should be undetectable after 16–24 weeks).
Viral load should also be checked 2–8 weeks after changing treatment. It may be possible to
monitor viral load and CD4 cell count every 6 months in those whose condition is stable after
2–3 years treatment.
Additional monitoring will depend on the antiretrovirals chosen and their potential adverse
effects.

35
 As some of the adverse effects of antiretrovirals have implications for cardiovascular disease
risk, monitor blood glucose and lipid concentrations regularly, especially if the patient has
other risk factors.
Consider monitoring drug concentration of NNRTIs and PIs (if available), eg to adjust doses
due to drug interactions or if virological response is not achieved. Assays can be done by the
Division of Clinical Pharmacology and Toxicology at St Vincent’s Hospital, Sydney.

:A. Nucleotide/Nucleoside reverse transcriptase inhibitors (NRTIs)

Zidovudine Stavudine Didanosine Tenofovir
Lamivudine Emtricitabine Zalcitabine Abacavir
‫زيدوا و اصطفوا لحسن ديدا حيطلع دين الميفودين و ساعتها نقول امتى يزل ابوه‬
.General characteristics: 1) All lack 3- hydroxyl group
They are inactive until phosphorylated by human kinases into active )2
.triphosphate metabolite
.All require dosage adjustment in renal insufficiency except Abacavir )3
All agents have black box warning concerning potential for development of )4
.Lactic acidosis, pancreatitis, neuropathy, liver toxicity & hepatomegaly with steatosis
Zidovudine .1 Approved for children & adults→ prevents prenatal infection in *
(azidothymidine/AZT .pregnancy
:)Or Retrovir .penetrates BBB*
S.E: bone marrow suppression→ so Erythropoietin is used (adjunct) *
: CI *
Probencid, Indomethacin & acetaminophen→ ↓ glucuronidation →↑ )1
AZT toxicity
Stavudine & Ribavirin are activated by same pathway→ so not given )2
.with AZT
:Stavudine (d4T) .2 crosses BBB S.E: neuropathy, lipoatrophy & hyperlipidemia *
:Didanosine (ddI).3 Crosses BBB but< AZT *taken on fasting state due to acid liability *
major SE: pancreatitis & neuropathy→ not taken with Stavudine *
:Tenofovir (TDF) .4 .Taken with meals→↑ bioavailability*
.Long t1/2→ once daily. S.E: GIT disturbances *
CI: 1)↑ Conc. of Didanosine
.conc. of Atazanavir→ so ritonavir is added ↓ )2
:Lamivudine (3TC) .5 .Used in comb. with Zidovudine for HIV*
Used in HBV*
:Emtricitabine (FTC) .6 .fluro derivative of Lamivudine (at least as effective as Lamivudine) *
.Long t1/2 *no interactions with other drugs *
.S.E (common):1) hyperpigmentation of soles & palms *
.Hepatomegaly & liver toxicity )2
Zalcitabine .7 .Removed from the market due to severe toxicity
:Abacavir (ABC) .8 .S.E: 1) GIT disturbances
.Hypersensitivity Rx→ in 5% of pts )2

:B. Non-nucleoside reverse transcriptase inhibitors [NNRTIs]

.Adv: 1) Selective non competitive inhibitors *
.They don't require activation by Kinase enzyme )2
.They lack effect on host cell mitochondria (i.e. no myelosupression) )3
.They lack cross resistance with NRTI )4
:Nevirapine (Nvp) .1 Due to hepatotoxicity→ shouldn't be used in women CD4+ T-cell *
.counts>250 cell/mm3 & in men > 400 cells/mm3

36
 .Not affected by food & antacids*
.penetrates to fetus, mother's milk &CNS *
Severe dermatologic S.E "Stephen Johnson syndrome"→14- day *
.titration period at a half dose is mandatory to ↓ risk of this S.E
.Inducer for cyp450*
:Delaviridine (DLv) .2 .cyp450 inhibitor *SE: rash (most common) *
:Efavirenz (EFv) .3 preferred NNRTIs by the guidelines *Bioavailability↑ by food *
t1/2=40hrs→once/day[ cyp450 inducer *SE: Vivid dreams, dizziness & rash (25% of pts) *
Teratogenic→ CI in pregnancy*
C. Protease Inhibitors (pIs):→ avir
Ritonavir Saquinavir Indinavir Nelfinavir Fosamprenavir
Lopinavir Atazanavir Tipranavir Darunavir
‫ريتا ادت صك لواحد هندي و قالتله تعالي نلف علي حسام نديله لوب و نقله ياخد اجازة تيبرا و يعد في داره‬
*M.O.A: Inhibit HIV-1 and HIV-2 proteases, preventing viral maturation and replication .
*Kinetics: 1. All have poor oral bioavailability so taken with fatty meals to improve oral bioavailability
Except Indinavir: fat meals↓↓ bioavailability.
*S.E:1.Nausea, vomiting& diarrhea. 2. Hyperglycemia.
3. ↑ cholesterol & triglycerides. 4. ↑ bleeding episodes
5. Body fat redistribution e.g. accumulation of fat at base of neck [buffalo hump] breast enlargement
6. Paresthesia [itching & reddening without physical cause].
*CI: All are competitive inhibitors of cyp450 (where Ritonavir →↑ potent inhibitor & Sequinavir → ↓
potent) so CI with the following drugs:
1. Antiarrythmics e.g. Quinidine 2.Ergot alkaloids e.g. Ergotamine
2. Antimycobacterial e.g. Rifampin 4. Benzodiazepines e.g. Triazolam & Midazolam
5. Inhaled steroids e.g. fluticasone 6. Herbal supplements e.g. St. John warts.
7. Statins e.g. Fluvastatin & simvastatin 7. Narcotics e.g. Fentanyl
:Ritonavir .1 Not used as protease inhibitor alone→ used as a pharmaceutical booster or *
.enhancer→ prevent level of resistance
.given with chocolate or milk or any food to improve palatability *
:Saquinavir .2 .used in combination with Ritonavir*
.t1/2 7-9hrs→ multiple dosing. *Fat meals→↑ absorption *
Soft gelatin capsules→ to ↑ oral bioavailability as it has lowest bioavailability of *
.all PIs (4%)
:Indinavir .3 shortest t/2 1.8hrs. *Gastric acidity is necessary for absorption (fat meals↓ *
abs.)
.Adequate hydration is important (1.5 L/day) → ↓ formation of kidney stones *
.Causes Hyperbilirubinemia*
:Nelfinavir .4 .t1/2: 5 hrs*
The only protease inhibitor that can't be boosted by Ritonavir because it is not *
extensively metabolized by cyp3A
.Given with Loperamide to avoid diarrhea. *has active metabolite *
Fosamprenavir .5 .long t1/2→ twice daily. *Ritonavir↑ plasma conc. & ↓ total daily dose *
Prodrug→ Amprenavir→ sulfonamide→cross sensitivity with other sulfa *
.drugs
:The formulation contains*
.Vit E so avoid other Vit E supplements .1
Propylene glycol→↑ amount causes toxicity so CI in some patients .2
:Lopinavir .6 ?Given with Ritonavir in one formulation……why *
.Because 1. Lopinavir→ short t1/2 2. Poor bioavailability
.N.B: 1.The formulation has 4:1 ratio of Lopinavir to Ritonavir
.Taken twice daily .2
The solution contains 42% alcohol so may cause disulfiram-like action .3
.with Metronidazole

37
 :Atazanavir .7 .the only once daily combination with Ritonavir. *Food ↑ absorption *
.Prolongs PR value & ↓ HR*
.CI with PPIs & H2 blockers→ dose spacing 12 hours*
S.E: jaundice*
:Tipranavir .8 .Useful in salvage regimens in pts resistant to multidrug regimens *
.Black box warning: 1. Severe & fatal hepatitis *
.intracranial hemorrhage ↑↑ .2
:Darunavir .9 Useful in salvage regimens
.PIs are approved for use in pediatrics *

:D. Fusion Inhibitors (Entry inhibitors)

:Enfuvirtide .1 It is fusion inhibitor (HIV must fuse its membrane with cell membrane of host cell in *
.order to gain entry into cells)
In combination with other antiretrovirals is approved for therapy of treatment *
.experienced with evidence of viral replication despite ttt with antiretroviral therapy
Take S.C*
.Must be reconstituted before use→ expensive *
.S.E: 1.Injection site reactions [nodules & pain] *
Hypersensitivity reaction [erythema] .2
.Pneumonia .3
:Maraviroc .2 .For CCR5 (co-receptor for fusion)-expressing virus *
.Absorbed orally*

:E. Integrase inhibitor

Raltegravir *M.O.A: Inhibits HIV integrase, which prevents viral replication by
stopping insertion of viral DNA into the host DNA.
*Twice daily
*as Enfuvirtide.

.N.B: Etravirine: → 2nd generation of NNRTIs

.Category B in pregnancy*
.Well tolerated with fewer CNS S.E*

38
39