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Lecture 10: Antibiotics &Anti-infective agents

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Microbiology:

Type of cells:

No Nucleus, No organelles.: Prokaryotes*

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

Well defined nucleus & membrane bound organelles. : Eukaryotes

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

they are extremely small microbes that are essentially fragments of nucleic Viruses:**

acid (DNA or RNA) packed in protein shells.

*Viruses are seen with electronic microscope only.

*Viruses are not living organisms, they are acellular.

they are also small prokaryotes but larger Chlamydia & Ricketssiae species:

than mycoplasmas.

*They have cell walls.

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

tissue. living

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

*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.

bacteria: of *Types

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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.

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

2) Vancomycin →taken orally "only case" for conditions that doesn't respond to

Metronidazole.

3) Cholestyramine resin may be used to bind bacterial Exotoxin.

Treatment M.O Infection is G penicillin1) Single ttt with

syphilis (no ry& 2 rycurative for 1

resistance).

is 2)Erythromycin or Doxycycline

used to treat pts allergic to penicillin

G.

Treponema palladium

spirochetes

(chancre) Syphilis

*single 200 mg doxycycline, given

within 72 hours after a tick bite can

prevent development of the disease.

*IV Ceftriaxone for severe cases.

Borrelia burgdorferi :disease Lyme

It's a disease that is transmitted

by bite of infected ticks.

skin *infections results in

fever & headache, lesions

followed by

meningoencephalitis &

arthritis.

Tetracycline Ricketsia rickettsi

**Typhus is characteristic of

rickettsial disease:

1. Epidemic typhus.

2. Murine (endemic) typhus.

3. Rocky mountain spotted

fever.

mountain Rocky

:fever spotted

Fever & aches in bones &

joints.

Erythromycin. 3AgNO Chlamydia trachomatus Eye infection in

neonate

Aminoglycosides Ps. Aeruginosa or St. aureus Adult eye infection

Polyvalent antitoxin Exotoxin of clostridium

botulinum

Botulism

No treatment Clostridium perfringens

cl. wekhii & cl. Noviji

Gas gangrene

Erythromycin Corynbacterium diphtheria Diphtheria

Legionella pneumophilia Legionnaire's disease

Rifampicin +INH (isonicotinic

hydrazide)+Ethambutol

Mycobacterium tuberculosis Granuloma,T.B

Penicillins

Neisseria meningitides, S.

pneumonia.

Adult meningitis

(epidemic)

H. influenza Infant meningitis

H. influenza, streptococcus B,

E. coli, Herpes simplex,

Lysteria, S. aureus (least

detected).

Neonatal meningitis

Penicillin +sulfoxazole

+Chloramphenicol

Meningococcal

encephalitis

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Penicillin St. aureus Toxic shock syndrome

(TTS)

E. coli, pseudomonas, staph,

klebsiella, Candida, proteus,

serratia.

Nosocomial infection

(Hospital acquired).

Metronidazole (flagyl, amrizole) -

quinacrine.

Tricomonas vaginalis (flag.

Protozoa)

Vaginal infection

Any antibiotic E. coli Most common UTI in

pregnancy.

*penicillin, Erythromycin

*Amoxicillin prophylactic

Streptococcus viridans Subacute endocarditis

associated with dental

problems.

Ceclor, Erythromycin + sulpha Strept. Pneumonia, H.

influenza

Ear infection> 4 years

E. coli, staph aureus Ear infection <4 years.

Famciclovir & vidarabin + calamine

oath bath

Herpes zoster Shingles disease

Tolnaftate, clotrimazole Fungus Athlete's foot (tinea

pedis)

Streptomycin +tetracycline Brucellosis &

toleramide

Erythromycin Chlamydia trachomatus ,

Strept & Neisseria gonorrhea

Blind conjunctivitis

Streptomycin IM, tetracycline (oral). Yersinia pestis Plague

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DNA Enzymes:

catalyze site specific cleavage of double strand 1. Restriction endonuclease:

DNA molecules.

5' G AATTC 3'

3'CCTTAA G5' Palindrome

N.B. They are used by bacteria to protect themselves against viral infection by

at cleavage site. Methylation

enzyme that hydrolyze phosphodiester bond from either 3' or 5' onuclease:2. Ex

terminus of polynucleotide molecule.

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

breaks in strands.

or ATP. +*requires energy in form of NAD

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

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

unwind DNA double strands :Helicase5.

relax supercoiled DNA→ How? :Topoisomerses6.

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.

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

initiation of DNA replication.

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a − Lactam & other Cell wall antibiotics:

* The cell wall is composed of: peptidoglycan polymer that consists of glycan+ peptide

cross linkage.

*Cell wall inhibitors require dividing M.O.

−Lactams:

Cephalosporins Penicillins:

th4

generation

rd3

generation

generation nd2 generation st1 *Amoxicillin

*Ampicillin

*Dicloxacillin

*Ticarcillin

*Piperacillin

*Oxacillin

*Methicillin

*Nafcillin

*Penicillin G

*Penicillin V

*Indanyl Carbenicillin

Cefipime Cefdinir

Cefixim

Cefotaxime

Ceftriaxone

Ceftazidime

Ceftizoxime

Ceftibuten

Cefaclor

Cefprozil

Cefuroxime

Cefoxitin

يروحوا عايزين وكستين

بروزيل فحطوا روكسى

كلور فيه للعرق

Cefadroxil

Cefazolin

Cephalexin

−Lactams inhibitor Others Monobactams Carbapenems

Clavulonic acid.

Sulbactam

Tazobactam

Bacitracin

Vancomycin

Daptomycin

Aztreonam Etrapenem

Imipenem / cilastatin

Meropenem

:Penicillins.1

interferes with last step of cell wall synthesis (cross linkage *Bactericidal→:M.O.A*

/transpeptidation).

located in the bacterial cytoplasmic →). penicillin binding proteins (PBPsa

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.

→ inhibition of cross linkage.b. Inhibition of transpeptidation reaction

→ autolysins are degenerative enzymes produced c. Production of autolysins

by the bacteria for normal remodeling in the cell wall & in the presence of penicillins

this action proceeds.

: Pharmacokinetics

1. Penicillins are excreted by kidney (excreted unchanged in urine) by active tubular

excretion →inhibited by probencid while Nafcillin is eliminated by biliary route.

2. Most penicillins are incompletely absorbed after oral administration except

Amoxicillin which is completely absorbed.

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penicillins are bactericidal bacterial spectrum:-Anti*

penetrated.: → cell wall is easily G+ve

→ envelope around cell wall, however porins permit entrance of penicillins. ve:-G

*Pseud. aeruginosa lacks porins → very resistant.

**Classification of Penicillins:

):1) Natural penicillins (penicillin G & V

streptococcus (pneumonia, pyogenes, viridans).→ G+ve cocci

→ Neisseria (gonorrhea, meningitides).ve cocci-G

→ Treponema palladium (syphilis).Spirochetes

Anaerobic→ Clostridium perfringens.

G+ve Bacilli→ Bacillus anthracis & Corynbacterium diphtheria.

*Penicillin V→ more acid stable.

Staphylococcal penicillins (Methicillin, Oxacillin, -2) Anti

afcillin, Dicloxacillin): [MOND]N

cillinase resistant penicillins.Peni

Used # penicillinase producing staphylococci.

MRSA→ by Vancomycin.

(Amoxicillin, Ampicillin)3) Extended spectrum:

.ve bacilli-The same spectrum of penicillin G with more effect on G*

moxicillin is the D.O.C of Lysteria monocytogenes (G+ve).A*

Used in combination with Clavulonic acid & Sulbactam respectively.*

pseudomonal penicillins: (Carbenicillin, Piperacillin, -Anti4)

[CPT] Ticarcillin)

* # Pseud. aeruginosa

* Ticarcillin + Clavulonic acid

* Piperacillin + Tazobactam

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

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*

1) − lactamase activity.

2) ↓ permeability to the drug (efflux pump).

3) Altering PBPs (as MRSA).

Routes of administration: *

→ IV & IMCPT & their combination*

→ oral.Penicillin V, Amoxicillin & Ampicillin +Clavulonic acid*

→ depot (IV).benzathine penicillin GProcaine penicillin G& *

60 mins).-→ given before food (30MOND*

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*Adverse effects:

→ most common. Hypersensitivity) 1

The metabolite penicilloic acid reacts with proteins→ Hapten that causes immune Rx.

pseudomembranous colitis.→ Diarrhea) 2

.mainly Methicillin →itisNephr) 3

→ epileptic patients at risk.Neurotoxicity4)

→ ↓ coagulation (CPT).Hematologic toxicities) 5

salt. +or K +penicillins are administered as Na: Cation toxicity6)

antiplatelet has it also & HTN of risk salt→↑ disodium as available is Ticarcillin N.B

bleeding. activity→

salt, disodium as available are products Carbenicillin & Ticarcillin **Although

CHF…Why? with patients of ttt in Carbenicillin over preferred is Ticarcillin

Carbenicillin. of that 1/2 is Ticarcillin of edos Because

(coombs test).7) Hemolytic anemia

Ampicillin after rash experience mononucleosis infectious with infected *patients N.B.

therapy.

Erythromycin. to shift but porincephalos to shift don't allergy penicillin with *patient

10%. is Cephalosporin & Penicillin between hypersensitivity *Cross

polylysine skin test. -→ Penicilloyl Test of penicillins Hypersensitivity:**

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.

bacterial spectrum:-*Anti

] = proteus mirabilis, resist [P/EC/K -→ as penicillin G, penicillinasegeneration st1*

E. coli, Klebsiella pneumonia.

+ Neisseria + aerogenes → G+ve (H. influenza+ Enterobactergeneration nd2*

[P/EC/K]. [H/E/N/P/EC/K].

Meningitis).ve (Ceftriaxone, Cefotaxime D.O.C for -→↓ G+ve, ↑Ggenerationrd *3

Ceftazidime→ pseudo. aerigonosa.

→ wide spectrum.generation th4*

as penicillins. *Uses:

→CSF→ Meningitis caused by H. influenza. Ceftriaxone, Cefotaxime**

Ceftriaxone is used in renal failure.

penetrates bone.→ prior to surgery, Cefazolin**

*Adverse effects:

especially with patients sensitive to penicillins. hypersensitivity) 1

like effects. Disulfiram2)

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[Ertapenem, Meropenem, Imipenem]: Carbapenems 3.

*Taken I.V & excreted renally.

"nephrotoxic". metabolite Toxic .peptidase enz Imipenem*

In kidney

(dehydropeptidase inhibitor in kidney). CilastatinImipenem + *

No toxic metabolites result from Imipenem→ used for UTIs.

bacterial spectrum:-Anti*

lactams.-are the broadest spectrum penemImipenem/Cilastatin & Mero

Used as empiric therapy.*

*Active# penicillinase producing G+ve, G-ve, anaerobes & p. aeruginosa.

.and diarrhea→ N, V, Imipenem/Cilastatin**Adverse effects:

High doses→ seizures. (Not seen with Meropenem).

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

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.

ic acid, Sulbactam &Tazobactam].[Clavulon :inhibitors Lactamase− 5.

*Binds with -lactamase enzyme with no antibacterial activity.

*In combination with −lactamase sensitive penicillins e.g. Amoxicillin+Clavulonic acid.

:antibiotics Other 6.

: → glycopeptides.Vancomycina)

:inhibit synthesis of cell wall :*M.O.A

1. Phospholipids

2. Prevent transglycosylation step in peptidoglycan polymerization.

renally. excretedby IV infusion & Taken*

&MRSE (Methicillin resistant staph. Epidermidis). # MRSA :Uses*

1. Oral form is limited for ttt of life threatening antibiotic associated colitis due to

clostridium defficile or staphylococci.

2. Quinopristin/ daflopristin &linezolid for Vancomycin resistant organisms.

3. Vancomycin + A.G. (synergism) → ttt of enterococcal endocarditis (E.E)

4. Vancomycin + Ceftriaxone → Meningitis.

2) ↓ binding to receptor. mediated changes in permeability.-1) Plasmid :*Resistance

1) fever effects: Adverse*

2) phlebitis in the infusion site

3) Flushing (red man syndrome)

4) Ototoxicity & nephrotoxicity when comb. With A.G.

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

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.

polypeptide antibiotic. → :) Bacitracinc

*Only Topically→ due to nephrotoxicity.

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:Synthesis Protein of Inhibitors B.

Macrolides4. Aminoglycosides3. Glycyclines2. Tetracyclines 1.

Azithromycin

Clarithromycin

Erythromycin

Telithromycin

Amikacin …..A

Gentamycin …G

Neomycin…..N

Streptomycin…S

Tobramycin….T

Kanamycin

Paromomycin

Tigecycline Tetracycline

Doxycycline

Minocycline

Demeclocycline

Achromycin V

8. Linezolid 7. Quinopristin/

daflopristin 6. Lincosamides Chloramphenicol . 5

Clindamycin

Lincomycin.

:Tetracyclines 1.

inhibit protein synthesis. binds reversibly to 30S ribosomal subunit→ M.O.A:*

*Pharmacokinetics:

shouldn't be taken with → 3+& Fe 2+, Al2+(dairy food) Mg 2+*Form chelates with Ca

food or antacids.

*They are metabolized in liver→ metabolites secreted in bile→ reabsorbed via

excretion by kidney. enterohepatic circulation →

half life. **So hepatic or renal dysfunction → ↑

**Doxycycline→ preferentially excreted via bile into feaces so can be used in renally

ffective in UTI.compromised patients.// ine

:Tetracyclines*Duration of action of

Doxycycline (20 h)>minocycline (19h)> Demeclocycline & methacycline (16h)>

oxytetracycline, chlortetracycline & tetracycline (9h).

Long acting agents→ lower & less frequent doses so↓ S.E.*

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

→ Vibrio cholera (Doxycycline).: Cholera1)

→ Borrelia burgdorferi (tick bite) →doxycycline 200mg. ) Lyme disease:2

→ Ricketssia ricketsii.3) Rocky mountain spotted fever

Trachomatus (sexually transmitted).Chlamydia → :4) Chlamydial infections

→ also with Macrolides. :5) Mycoplasma pneumonia

*Resistance:

1) Inability of the organism to accumulate the drug by efflux mechanism.

2) Any organism resistant to one tetracycline is resistant to all.

3) Most penicillinase producing staph are resistant to Tetracyclines.

*Adverse effects:

→ taken with food not dairy. 1) Gastric discomfort

→ discoloration of teeth & staning of growth.2) Calcified tissue

damage. renal& hepatotoxicity3) Fatal

→ severe sunburn.Phototoxicity4)

→ Minocycline & Doxycycline.Vestibular problems 5)

→ ↑ intracranial HTN.6) Pseudomotor cerebri

→ Candida (vagina).7) Superinfection

Staph (intestine).

Clostridium defficile (pseud. colitis)

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

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Tigecycline :Glycyclines 2.

*Derivative to Minocycline.

*Used in complicated skin & soft tissue infections (as Daptomycin) & intrabdominal

infections.

.as tetracycline :*M.O.A

ve-lactamase producing G-→ MRSA, VRE & *Antibacterial spectrum:

Not active # proteus, providencia & pseudo. (3p).

→ IV infusion /12hrs. *Dose: *Adverse effects:

problems→ nausea & vomiting. 1) Vestibular

Photosensitivity.2)

3) Teeth discoloration.

4) C.I→ Pregnancy. * Interactions:

1) Not with oral contraceptives.

2) ↑ Warfarin conc.

:Aminoglycosides 3.

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

The bactericidal effect is conc. & time dependant so bacterial spectrum:-* Anti

↑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).

1) ↓ drug uptake. * Resistance:

2) Enzymes synthesis that modifies or inactivates antibiotic → Amikacin is less

susceptible to these enzymes.

All are given parenterally except Neomycin→ topical only :Administration*

because it is severely nephrotoxic.

.filtrationy unchanged by Glomerular they are excreted renall *Excretion:

N.B Amikacin differs from others that:

1) Broadest spectrum G-ve bacilli.

2) Least susceptible to bacterial enzymes that inactivate aminoglycosides. toxicity:**Maximum Gentamycin serum level that doesn't cause

1) For traditional dosing→ 10g/ml. 2) For once daily dosing→ 20g/ml.

*Adverse effects:

cranial th→ damage to cochlear & vestibular portions of auditory nerve [81) Ototoxicity

nerve].

2) Nephrotoxicity

paralysis→ ↓ Ach release from presynaptic nerve ending.3) Neuromuscular

4) Allergic reactions→ contact dermatitis with topically applied Neomycin.

Myasthenia gravis →to reverse block take calcium gluconate or Neostigmine. :*C.I

→ polypeptide structure Viomycin 1. N.B.

*it shares some properties with streptomycin (i.e. both have anti T.B. activity).

Viomycin is closely related in structure to streptomycin (F) (T) or (F): Q) Put

.Polymyxin B & Colistinpeptide Abs: poly 2. Other

M.O.A: disrupting of m.o cytoplasmic membrane.

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Spectrum: G-ve organisms.

S.E: nephrotoxicity

:Macrolides 4.

binds irreversibly to 50S ribosomal subunit→ inhibit protein synthesis. :M.O.A*

ketolide (in macrolide resistant G+ve) stTelithromycin→ 1

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

as penicillin G. :1) Erythromycin

D.O.C in Chlamydia during pregnancy.

as Erythromycin. :2) Clarithromycin

# H. Influenza, H- pylori, Chlamydia, Legionella, Moraxella & ureaplasma (CHULMH).

→ respiratory tract infections (H. influenza & Moraxella). :3) Azithromycin

Preferred in urethritis caused by Chlamydia.

: similar to Azithromycin.4) Telithromycin

Neutralizes all resistance mechanisms.

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

1) presence of Efflux mechanism. *Resistance:

2) ↓ affinity to 50S ribosomal subunit.

3) Plasmid mediated erythromycin resistance (Azi& clari).

Telithromycin # resistant strains.

*They are taken orally. *Pharmacokinetics:

*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:

Clarithromycin & Azithromycin are → with Erythromycin but distress ) Epigastric1

better tolerated.

→ with Erythromycin. Ototoxicity2)

occurs with the estolate form of Erythromycin due to ) Cholestatic Jaundice →3

hypersensitivity Rx.

*C.I:

1) Hepatic dysfunction.

2) Telithromycin→ Myasthenia gravis.

:Chloramphenicol 5.

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

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

aeruginosa.

inactivate A transferase→ may ctor that encodes for acetyl CoR fa *Resistance:

Chloramphenicol.

anemia. 1) Anemia & Aplastic *Adverse effects:

2) Gray baby syndrome→ cyanosis & death.

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

O.2→ it dissolves in H: Clindamycin 6.

ribosomal subunit.Binds to 50S M.O.A:*

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

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

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

Vancomycin)→ diarrhea.

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

50S separate site on to sbindEach component of this combination drug :*M.O.A

ribosomal subunit→ Synergism→ bactericidal.

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

) efflux pump.a :Resistance*

b) plasmid-mediated transferase inactivates daflopristin.

c) Ribosomal enzyme interferes with Quinopristin binding.

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

1) Venous irritation. * Adverse effects:

2) Arthralgia & Myalgia.

3) Hyperbilirubinemia →↑ total bilirubin due to competing with

antibiotic for excretion.

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

:Linezolid 8.

inhibit near the interface with 30s subunit → Binds to 50s ribosomal subunit M.O.A:*

formation of 70s initiation complex inhibits protein synthesis.

MRSA, VRE (faecalis & faecium) & penicillin resistant streptococci. *Spectrum:

*# Mycobacterium tuberculosis & Lysteria monocytogenes &

Corynbacterium.

**No effect on cyp450.

1) Rash. :*Adverse effects

2) Thrombocytopenia if the drug is taken > 2 weeks.

3) GIT, nausea & diarrhea.

Aminoglycosides only inhibitors synthesis protein all Among N.B.

bacteriostatic. are others while bactericidal are

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C. Quinolones, Folic Acid Antagonists, &

Urinary Tract Antiseptics:

U.T

Antiseptics

Combination Inhibitors of

Folate

reduction

Inhibitors of

Folate synthesis

(Sulfonamides)

Fluroquinolones

*Nitrofurantoin

*Methenamine

*Cotrimoxazole *Trimethoprime

*Pyrimethamine

*silver sulfadiazine

*Sulfadiazine.

*Sulfamethoxazole.

*Sulfasalazine.

*Sulfacetamide.

*Sulfisoxazole.

*Succinyl-

sulfathiazole.

*Mafenide.

Nalidixic generation st1

à generation: nd2

Ciprofloxacin Norfloxacin

Ofloxacin. generation rd3

Levofloxacin. Gatfloxacin

Sparfloxacin

:generation th4

Moxifloxacin Trovafloxacin

:Fluroquinolones 1.

They inhibit replication of bacterial DNA by interfering with DNA gyrase M.O.A:*

(Topoisomerase II) & Topoisomerase IV.

seudo, H. influenza & Moraxella.ve as p-1) Active # G Spectrum:*

ve.-→ Gst 2) 1

ve, G+ve & atypical org. (Mycoplasma pneum & Chlamydia pneum.).-→ G nd3) 2

ve, ↑ G+ve & atypical org.-→ G rd4) 3

G+ve & anaerobes.↑ ve, -G→ th5) 4

1) D.O.C → Anthrax

2) Resp. tract infection→ NOT D.O.C →weak # Strept pneum.

3) UTI 4)Gonorrhea 5)GIT infections

6) The most potent Quinolone # pseudomonas aeruginosa

Ciprofloxacin

1) # G-ve (pseudo aerug.)

2) G+ve UTI & Prostatitis.

Norfloxacin

1) Gonorrhea 2) Prostatitis (E. Coli)

3) Acute bronchitis 4) RTI (S. pneumonia)

Levofloxacin

1) ↑ G+ve 2) Anaerobes

3) Weak # pseudo. aeruginosa.

Moxifloxacin

All can be taken orally except Trovafloxacin→ taken IV. :Route*

with once 1/2N.B. Levofloxacin, Moxifloxacin, Sparfloxacin & Trovafloxacin → long t

daily dosing.

gyrase.of DNA 1) Mutation :Resistance*

2) ↓ accumulation due to ↓ porins & efflux pump. * Pharmacokinetics:

→ interfere with the absorption of Quinolones.2+& Mg 3+, Fe2+, Zn3+, Al2+1) Ca

N.B Nalidixic acid: ↓ absorption by food or antacid & common S.E is visual

disturbances.

Adverse Effects:*

→ nausea, vomiting & diarrhea.GIT 1)

→ headache & dizziness especially with Ciprofloxacin.CNS 2)

→ so avoid excessive sunlight & apply sunscreens. Phototoxicity 3)

(Arthropathy).→ CI < 18 years problems tissue Connective 4)

CI in pregnancy & lactation.

→ Trovafloxacin.toxicity Liver 5)

→ CI in arrhythmia. → (↑ QTC) Sparfloxacin & Moxifloxacin 6)

18

.→↑ Theophylline Ofloxacin & Ciprofloxacin 7)

Caffeine.→↑ Warfarin, cyclosporine & th4 & rd3

:Sulfonamides → synthesis Folate of Inhibitors 2.

analogues (have structural similarity) of PABA so they compete with PABA *M.O.A:

for the bacterial enzyme dihydropteroate synthetase → inhibit the synthesis of

bacterial dihydrofolic acid (↓ DHF). :*Pharmacokinetics

ine which isn't absorbed so used for ttt all are absorbed except Sulfasalaz :1) Orally

of chronic inflammatory bowel disease e.g. Crohn's disease or Ulcerative colitis.

Sulfasalazine Intestinal Sulfapyridine + 5 aminosalicylate (antiinflam. effect)

Flora

→ ttt of burn associated sepsissilver sulfadiazine or Mafenide acetate *Creams:

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.

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

Sulfadiazine + Pyrimethamine → Toxoplasmosis & chloroquine resistant malaria

tasetered dihydropteroate synthe1) Al *Resistance:

2) ↓ Permeability of the drug.

3) ↑ production of natural PABA.

*Adverse effects:

ow to overcome?→ may cause nephrotoxicity → H Crystalluria 1)

**By: Adequate hydration & alkalinization of urine

*Newer agents such as Sulfamethoxazole & Sulfisoxazole are more soluble at Urinary

pH than older sulphonamides → No Crystalluria.

: such as rash, angiodema & Steven Johnson syndrome.Hypersensitivity 2)

phosphate dehydrogenase -6-in patients with Glucose :anemia Hemolytic 3)

deficiency.

: In new born→ sulfa displaces bilirubin → crosses BBB.Kernicterus 4)

, ↑Warfarin.Methotrexate , ↑↑Tolbutamide (hypoglycemia) :potentiation Drug 5)

wborns <2 months & pregnancy due to → Ne (not with Methenamine (condense)) CI 6)

risk of kernicterus.

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

Trimethoprim. & Pyrimethamine → reduction Folate of Inhibitors .3

M.O.A:*

tsyn à amino & thymidine purine, acid Tetrahydrofolic dihydrofolate à olicF

reductase.

This mechanism occurs for both human & microorganisms.

50 folds more potent than sulfonamides. -20 :Spectrum*

1) Alteration of dihydrofolate reductase. :Resistance*

2) Over production of enzyme.

19

& Methotrexate in cancer & R.APyrimethamine in parasitic infections :Uses*

Megaloblastic anemia, Leukopenia & granulocytosis * Adverse effects:

(symptoms of folic acid deficiency) → ttt with Folinic acid.

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

3) GIT1) UTI 2) RTI :*Spectrum

4) Lysteria monocytogenes (septicemia & meningitis).

5) Pneumocystis jiroveci pneumonia (AIDs).

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

3) Dermatologic.

:antiseptics tract Urinary 5.

*Pathogens that may cause UTI are:

3)Staph. saprophyticus 1) E.coli 2) Proteus mirabilis

4) Klebsiella pneumonia.

: Hexamine Hippurate.Methenamine A.

*M.O.A:

Formaldehyde + ammonium ions. at acidic sdecompose Methenamine*

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.

# lower UTIs not upper UTIs. *Spectrum:

Not # proteus.

2) Hematuria 1) GIT distress *Adverse effects:

3) Albuminurea 4) Rashes

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

→ CNS toxicity.

2) Patients with renal insufficiency because mandelic acid may precipitate.

3) With Sulphonamides→ because sulfonamides react with formaldehyde.

E.coli : #Nitrofurantoin B.

*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:

1. Nitrofurazone (topically) &2. Furazolidone (local action).

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

→ 1.UT anesthetic available only as oral D.F & analgesic.PhenazopyridineN.B.

2. Causes reddish discoloration of urine.

3. Not used more than 2 days→ WHY?

Because it would mask pain that might be indication of failure of antimicrobial

therapy.

].5: elevated nitrite level in the urine [bacteria count 10uriaBacter*

20

Tested by Microstix.

ttt of UTIs by large single doses of drugs:*

1. Amoxicillin: 3g

2. Fosfomycin: 3g

Antibiotics: & **Pregnancy

cross placental barrier but none has been shown to be : All*Penicillins

teratogenic.

: CI……….Why?*Tetracyclines

Discoloration & hypoplasia of neonatal teeth & hepatotoxicity to mother.

: cross placental barrier & may lead to Ototoxicity & *Aminoglycosides

nephrotoxicity of newborn.

"Grey baby syndrome"→ why? hloramphenicol:*C

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.

pregnancy, lactation & children < 18 years why?CI *Fluroquinolones:

Because it causes connective tissue problems → articular cartilage erosion

"Arthropathy".

CI pregnancy, newborns & infants < 2 months why? *Sulfonamides:

Sulfa drugs displace bilirubin from binding sites on serum albumin → free

bilirubin→ pass into CNS BBB of baby isn't fully developed → Kernicterus.

: it produces the effects of Folic acid deficiency → Megaloblastic *Trimethoprim

anemia, leukopenia & granulocytopenia so CI in pregnancy.

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

Important extra notes:

*Agents active against Helicobacter pylori:

1. Clarithromycin. 2. Tetracycline

3. Metronidazole 4. Bismuth subsalicylate.

→ H. influenza & S. :*The best product for ttt of Otitis media

pneumonia are major causes of Otitis media & sinusitis

1. Trimethoprime/ Sulfamethoxazole

2. Amoxicillin or Ampicillin.

are more effective in ttt CNS generation cephalosporins rd*3

generation e.g. Ceftriaxone & ndor 2 stinfections such as meningitis than 1

Cefotaxime.

: is indicated for decreasing Phthalylsulfathiazole*

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.

21

D. Antimycobacterial Drugs:

Leprosy T.B

Dapson+ Rifampin+ Clofazimin line nd2 line: st1

Aminoglycosides

Fluroquinolones

Macrolides

Cycloserine

Aminosalicylic acid

Capreomycin

Ethionamide

Ethambutol

Pyrazinamide

Rifamycin

Isoniazide

*6 months therapy.

*2 months→ Isoniazide, Rifampin, Pyrazinamide & Ethambutol.

*40 months→ INH + Rifampin

applied to ↓ resistance & improve ) → system Direct observed therapy (DOT*

recovery.

24 months)-(takes 6**The purpose of combination drug ttt in T.B:

1. Delay emergence of drug resistance.

2. ↑ tuberculostatic effects of the drug e.g. Streptomycin & Isoniazide.

Q) Put (T) or (F):

Drug combination for T.B reduces the duration of therapy (F).

Line treatment: st1

icotinic acid → it is the hydrazide of ison"INH": Isoniazide 1)

(synthetic analog of pyridoxine).

synthesisnhibits bacterial cell wall synthesis by inhibiting mycolic acid I :M.O.A

(by inhibiting InhA & KasA which are important in mycolic acid synthesis).

*INH is deactivated by bacterial Kat G.

1) Mutation in Kat G :Resistance

2) Overexpression of InhA.

3+rbohydrates & AlAffected by food especially Ca Pharmacokinetics:

containing antacids.

(pyridoxine). 6Peripheral neuritis→ ttt with Vit B 1) :Adverse effects

2) Hepatotoxicity→ most severe S.E.is due to conversion by

phase II reaction into more toxic metabolite.

3) ↑ effect of Phenytoin (inhibit metabolism)

Nystagmus & Ataxia.

tylator of Isoniazide is who is slow ace PatientA characterized by:

1. Slow metabolism but normal therapeutic response.

2. More likely to develop peripheral neuropathy but respond well to ttt with Vit.

.6B

So metabolism is in liver & metabolic products & some unchanged drug are

excreted by kidney.

22

Metabolites: acetylated form + isonicotinic acid.

2) Rifamycins: → Rifampin, Rifabutin & Rifapentin.

A) Rifampin:

inhibit mRNA synthesis. : inhibit RNA polymerase M.O.A*

ve.-kanasii, G+ve, G #M.TB, M. Spectrum:*

Used in prophylaxis of meningitis caused by H. influenza.

Most active anti leprosy agent.

1) mutation in RNA polymerase. *Resistance:

2) ↓ permeability.

**Warning: 1) may stain urine & feaces red color.

2) Tears may permanently stain soft contact lenses orange-red.

1) nausea & vomiting. *Adverse effects:

2) Liver dysfunction with elderly & alcoholics.

3) May cause influenza like syndrome "rare.

4) Rash so monitor CBC.

lism of oral contraceptives, oral anticoagulants, "Enzyme inducer"→ ↑ metabo *Drug interactions:

prednisone, propranolol, Digoxin, ketoconazole, sulfonylurea, Quinidine & Clofibrate.

C) Rifapentin:

than Rifampin & Rifabutin 1/2Longer t

*2 months→ twice weekly.

*4 months→ once weekly.

*never used alone (used in combination to avoid resistance).

B) Rifabutin:

*D.O.C In the ttt of T.B in which patient is

infected with HIV.

S.E: As Rifampin + hyperpigmentation of

skin+ Neutropenia.

:Pyrazinamide 3)

"active form". acid Pyrazinoicbacterial pyrazinamidase Pyrazinamide*

hydrolysis

*Some resistant strains lack pyrazinamidase.

*active # tubercle bacilli.

*Both Pyrazinamide & Ethambutol→ cause urate retention→ exacerbate gout.

: Ethambutol 4)

*Active # M. tuberculosis & M. kanasii.

inhibits cell wall synthesis. : It inhibits arabinosyl transferase enzyme *M.O.A

which results in diminished visual acuity & Optic neuritis1) *Adverse effects:

loss of ability to differentiate between green & red.

.Gouty attacks2)

Line treatment: nd2 antibiotic to treat T.B st1) 1

2) Streptomycin resistant strains→ Amikacin & Kanamycin.

1. Streptomycin:

Preserved for multi drug resistant strains.

May cause Ototoxicity & nephrotoxicity.

2. Capreomycin

(Parenterally)

Causes CNS disturbances & peripheral neuritis → pyridoxine. 3) Cycloserine

*structural analog of INH & inhibits Acetylation of INH.

*Peripheral neuritis & optic neuritis→ pyridoxine.

4) Ethionamide:

23

Moxifloxacin & Levofloxacin. 5)

Fluroquinolones

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

E. Antifungal Drugs: ttt of Cutaneous Mycoses ttt of Subcutaneous & Systemic Mycosis

1. Terconazole.

2. Econazole.

3. Butoconazole.

4. Clotrimazole.

5. Miconazole.

6. Griseofulvin

7. Nystatin.

8. Terbinafine.

1. Fluconazole.

2. Ketoconazole.

3. Voriconazole.

4. Itraconazole.

5. Posaconazole

6. Micofungin.

7. Anidulafungin.

8. Caspofungin

9. Flucytosin

10. Amphotercin B

A. Drugs for subcutaneous & Systemic Mycosis:

:B Amphotercin 1.

*D.O.C in ttt of life threatening systemic Mycoses.

*Can be used in combination with Flucytosin to ↓ conc. of Amphotercin B.

binds with ergosterol in fungal cell membrane→ forms pores→ loss of :*M.O.A

& leakage of electrolytes→ fungal cell death. +K

s neoformans, coccidioides Candida Albicans, Cryptococcu Spectrum:*

immitis, Blastomyces dermatitidis & Histoplasma capsulatum.

*Also used in ttt of protozoal infections, Leshmeniasis.

Pharmacokinetics:*

1) By slow IV infusion.

2) Formulated as lipid formulations:

Amphotercin B + Liposomes→ liposomal Amphotercin B

Adv: ↓ Nephrotoxicity & infusion toxicity.

E.g. AmBiSome, Abelcet & Amphotec.

3)When renal dysfunction occurs due to Amphotercin B→ dose reduction to

50%.

↓ ergosterol content of the fungal membrane (rare). *Resistance: * Adverse effects:

use antipyretic or → 3 hours of administration-after 1→ 1) Fever & Chills

corticosteroids. 2+& Mg +: ↓ Cr cl, ↓K2) Renal impairment

IV infusion of saline before & after drug→ ↓ renal impairment.

supplement is required. +K CI with digitalis :3) Hypotension & Hypokalemia

: ↓ erythrocytes production (exacerbated in AIDs pts taking Anemia)

Zidovudine).

after intrathecal injection.: 5) Neurologic effects

: So add Heparin to the infusion fluid.6) Thrombophlebitis

FC):-(5 Flucytosin 2. Synthetic pyrimidine forms a false nucleotide that inhibits thymidylate *M.O.A:

synthesis → Thymidylic acid → ↓ DNA synthesis.

24

In combination with Amphotercin B→ Cryptococcus reformans 1):*Spectrum

& Candida Albicans→ Meningitis.

2) In combination with Itraconazole→ Chromoblastomycosis.

Penetrates CSF. Oral route. :Pharmacokinetics*

2)Thrombocytopenia utropenia 1) Ne Adverse effects:*

3) Bone marrow depression 4) GIT disturbances.

3. Azoles:

Posaconazole Voriconazole

Itraconazole

Fluconazole Ketoconazole

: they block cyp450 enzyme imp.Ergosteroldemethylation Lanosterol

Cyp450 for demethylation of Lanosterol

M.O.A:

Oral ,IV Oral Oral, IV Oral Routes

--------- ----- No Yes No CSF

penetration

------- ------ No Yes No Renal

excretion

-------- ------ Expanded Expanded Narrow Spectrum

All are teratogenic so CI in the pregnancy Pregnancy

Nausea, vomiting, rashes & Hepatitis [rare].

only: inhibits human gonadal & adrenal steroid synthesis leading to ↓ Ketoconazole

testosterone & cortisol production→ Gynecomastia, Libido, impotence & menstrual

irregularities.

S.E:

All are inhibitors of cyp450 enzyme of human with ketoconazole being the most

potent. e.g. ↑ toxicity of some drugs with Theophylline.

DI

*administered

with meals.

*ttt of oroph.

candida→ once

daily.

*prophylaxis→ 3

times daily.

*may cause

transient

visual

disturbance

*Itraconazol

e + 5fc→ttt

of

Chromoblas

tomycosis.

*D.O.C for

aspragillosis

, sporotri-

chosis &

paracoccidi

oidomycosis.

*D.O.C for

1)

Cryptococc

us

neoformans.

2)candidemi

a

3)

Coccidioido

mycosis.

**used

prophylactic

ally to ↓

fungal

infections in

bone

marrow

transplants

*it requires

gastric acid for

absorption so

any drug ↓

gastric à→↓

absorption.

*Ketoconazole &

amphotercin B

shouldn't be used

together….why?

Because

ketoconazole↓

ergosterol in

fungal memb.→↓

fungicidal action

of Amphotercin

B

Notes

N.B: Drug interactions with ketoconazole:

receptor blockers, PPIs→↓ acid→↓ absorption. 21. Antacids, H

2. Food→ ↓ absorption.

3. Amphotercin B

4. Ketoconazole inhibits metabolism of Cisapride, astemizole & terfinadine →↑ plasma

level→ Arrhythmia {Torsade de points}.

4. Echinocandins:

inhibit cell glycan→ -(1,3)D inhibit *M.O.A:

wall synthesis

1. Caspofungin

(not orally)

25

limited to Aspragellus & candida. spectrum:*

Rash, nausea, vomiting & flushing (due to *SE:

histamine release).

N.B. Shouldn't be administered with Cyclosporine.

*not active orally but IV infusion.

*Histamine mediated S.E.

2. Micofungin &

Anidulafungin

B. Drugs for Cutaneous Mycoses:

**Superficial skin infections are called dermatophytes e.g. tinea "ring worm".

Griseofulvin 2. Terbinafine 1.

Inhibition of mitosis of fungal

cell "Fungistatic"

Inhibits squalene epoxidase enzyme

necessary for synthesis of ergosterol→

inhibit ergosterol formation.

*also accumulation of squalene→ cell

death "fungicidal"

M.O.A:

As Terbinafine but

Terbinafine replaced it

because it is more effective,

also for tinea capitis.

ttt duration:6-12 months

D.O.C for ttt of dermatophytes

especially "Onchomycosis [fungal

infection of nails]

ttt duration: 3 months

Spectrum

Oral & absorption ↑ by high

fat meal

Orally active with bioavailability 40 %

pass effect stdue to 1

Route

*exacerbate intermittent

porphyria.

*Not taken with alcohol→↑

toxicity

Nausea, diarrhea, rash, hepatitis

(rare).*

*taste & visual disturbances

S.E:

**It is Enzyme inducer Rifampin→↓blood level of Terbinafine.

Cimetidine→↑ blood level of

Terbinafine.

D.I

:→polyene antibiotic with same characteristics of Amphotercin BNystatin 3.

*oral wash for oral candidiasis

Butoconazole & Terconazole clotrimazole, Miconazole, 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

26

F. Anti-protozoal Drugs:

*Life cycle of Entamoeba histolytica: :Amebiasis 1.

Drugs : Clinical syndrome:

or Paromycin or Diloxanide furoate Iodoquinol 1. Asymptomatic cyst carriers:

Metronidazole + Iodoquinol or Paromycin or

Diloxanide furoate.

Diarrhea/Dysentery . 2

"Extraintestinal"

Chloroquine + Metronidazole or Emetine. 3. Amebic Liver abscess:

Comment: Drug:

: destruction of helical structure of DNA.*M.O.A

1) ttt of Giardiasis (D.O.C). *Other uses:

2) Trichomonas vaginalis

3) Anaerobic→ Bacteroids species "C. defficile/

pseudomonas colitis".

1. Epigastric distress, nausea & vomiting "most common" S.E:

2. Unpleasant metallic taste.

3. CNS dizziness & numbness "rare".

4. If taken with alcohol→ disulfiram-like effects.

5. Urine turn red brown color.

1. Metronidazole

"mixed ameobicide"

(flagyl)®

1. Rash. S.E:

2. High dose long term use: peripheral neuropathy & optic

neuritis.

3. May interfere with the results of thyroid tests.

2. Iodoquinol

Mild "Dry mouth, flatulence & Urticaria". S.E:

Pregnancy & children < 2 years. C.I:

3. Diloxanide furoate

Aminoglycoside antibiotic→ protein synthesis inhibitor. M.O.A:

Taken orally with insignificant absorption so S.E include only S.E:

GIT distress & diarrhea.

4. Paromomycin

27

They are alkaloids obtained from Ipecac→ They kill amebae M.O.A:

by inhibiting protein synthesis.

1. Taken I.M→ pain at injection site. S.E:

2. Toxicity: CVS [arrhythmia & CHF].

Neuromuscular weakness.

5. Emetine &

Dehydroemetine

:Malaria 2.

parasite:*Life cycle of the malaria

→ Sporozoites migrate to the liver, where they SporozoitesAn infected mosquito injects

→ Merozoites are released & invade red blood cells→ in the red blood itesomerozform

→ Trophozoite use Hb as nutrient→ trophozoitecell, the merozoite becomes a

Trophozoites multiply producing new merozoites→ merozoites infect other RBCs or

uito picks up gametocyte from an infected human→ → female mosqgametocytesbecome

sexual cycle occur in mosquito & form sporozoite.

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

2. Orthostatic hypotension.

3. Massive erythrocytosis [abnormal elevation of RBCs]

→ drug is effective against exoerythrocytic form.schizonticide Tissue 1) ttt:

erythrocytic form.→ drug is effective against schizonticide Blood 2)

Chloroquine [4- aminoquinoline] All plasmodium species except

chloroquine resistant P. Falciparum

Quinine +Pyrimethamine/ Sulfadoxine or Doxycycline or

Clindamycin

Alternate: Mefloquine

Chloroquine resistant

P. Falciparum

Primaquine Prevention of relapses:

P. vivax & P. ovale only

*Chloroquine sensitive geographic areas: Chloroquine.

*Chloroquine resistant geographic areas: Mefloquine.

Prevention of malaria

Chloroquine or Mefloquine Pregnancy

Comment Drug

phosphate -6-induced hemolytic anemia in pts with G: 1. Drug S.E

dehydrogenase deficiency.

2. Abdominal discomfort especially if taken with Chloroquine.

: in patients with Rheumatoid arthritis & Lupus erythromatoses.C.I

A. Tissue

schizonticide:

Primaquine

digestion by the Hb: M.O.A*

"food for the parasite" acids Amino arasiteP

"toxic to the parasite" Heme

Chloroquine (-) polymerization by the parasite

"untoxic" Hemozoin

N.B: chloroquine has anti-inflammatory action so may be used in Rheumatoid

arthritis & lupus erythematosues.

it concentrates in liver so use with caution in Hepatic disease. :1) bec.S.E

2) Used with caution in patients with GIT, neurologic or blood disorder.

3) Ophthalmologic examination should be routinely performed due to visual

disturbances.

C.I: in patients with psoriasis or porphyria.

DI: with Gold or Phenylbutazone→ aggravation of dermatitis.

B. Blood

schizonticide:

1. Chloroquine:

*If Mefloquine is taken with quinine or quinidine→ cardiac arrest.

*If Mefloquine is taken with quinine or chloroquine→↑ risk of convulsions

2. Mefloquine

28

1. Cinchonism "tinnitus, vertigo & nausea". :S.E

phosphate dehydrogenase deficiency & ttt is -6-in patients with Glucose C.I:

stopped if +Coombs test for hemolytic anemia occurs.

DI: 1) with neuromuscular blockers→ potentiation

2) with Digoxin→ ↑digoxin level so ↓ dose by 1/2

3) With Al antacids→ related quinine absorption.

3. Quinine &

Quinidine:

*It's also active against T. gonadii.

S.E: May cause fatal hypersensitivity reactions.

4. Fansidar

For ttt of multidrug resistant P. Falciparum 5. Artemsinin

الصينى الطب

N.B: If it causes megaloblastic anemia→ ttt with Leucoverin (protects against

folate deficiency).

6.Pyrimethamine

cause Toxoplasma gonadii. Toxoplasmosis: 3.

ttt: Pyrimethamine / Sulfadiazine & Fansidar.

N.B: At first appearance of rash Pyrimethamine should be discontinued because it may

cause severe hypersensitivity → Fatal.

"transmitted by infected sandflies" Leshmaniasis: 4.

ttt: Na stibogluconate: taken IV

S.E: pain at injection site & cardiac arrhythmia.

*Pentamide+ Amphotercin B as backup.

*Allopurinol: may be effective.

s:Trypanosomiasi 5.

African:

.brucei TrypanosomaCaused by

Transmitted by bite of Tsetse fly "sleeping sickness"

:American

Caused by

.cruzi Trypanosoma

.gambiense T. brucei*

*Slow to enter the CNS.

rhodesiense. T. brucei*

*Early invasion of CNS.

*Fatal if not treated

*Called Chagas disease.

*transmitted by insect

feces contaminating eye

or skin lesions.

*Causes

cardiomyopathy

Surdmin ttt Pentamidine Isethionate ttt Melarsoprol ttt Nitrofurtimox

*Paresthesia of

hands & feet.

*Edema of

eyelid.

*Nausea &

vomiting of GIT.

*Albuminurea:

If renal casts or

Hematuria

occur→cease ttt.

*Shock & loss of

consciousness

due to

hypersensitivity.

*M.O.A: inhibition of DNA,

RNA, Phospholipids& protein

synthesis of Pneumocystis

crainii (PCP).

*S.E: 1. It is taken either by

aerosol, I.M or I.V

a)Aerosol: cough &

bronchospasm.

b) Parentral: severe

hypotension.

2. Nephrotoxicity.

3. Toxic to cells of the

pancreas→ may cause

reversible IDDM.

*Unlike Pentamidine it

penetrates CSF so used

T.brucei rhodesiensefor

& meningoencephalitis

T.bruceicaused by

.gambiense

*S.E: 1) CNS toxicity e.g.

encephalopathy.

2) After injection:

hypersensitivity Rx, fever

& severe vomiting.

C.I: 1) pts with influenza

*Suppressive

*M.O.A: it undergoes

reduction→ generates

oxygen radicals→ toxic

to T.cruzi.

*S.E:1) immediate

hypersensitivity Rx e.g.

anaphylaxis.

2) Delayed

hypersensitivity Rx e.g.

dermatitis.

3) Severe GIT problems

that may cause wt loss.

29

2) Pts with Glucose-

6-phosphate

dehydrogenase deficiency.

4) Peripheral

neuropathy (common).

G. Antihelmentic Drugs:

Cestodes Trematodes Nematodes

Albendazole

Niclosamide

Praziquantel Mebendazole

Thiobendazole

Ivermectine

Pyrantel pamoate

Diethyl carbamazine

:Nematodes for Drugs I.

Diethyl-

carbamazine

Ivermectine Pyrantel

pamoate

Thiobendazole Mebendazole

Immobilize the

parasite &

render them

susceptible to

host defense

influx→ -↑ Cl

hyperpolarizatio

n

→ Worm

paralysis.

Depolarizing

NMB→

paralysis of

worm→

expelled with

feces

Interferes with parasites

microtubule &↓ glucose uptake

M.O.A

*Filariasis:

(wucheria

bancrofti &

Brugia Malayi)

in combination

with

Albendazole

D.O.C in:

1. Onchocerciasis

(River blindness).

2. Thread worm

(Strongyloides

stercoralis).

In combination

with

Mebendazole #

round, pin &

hook worms

1. Thread worm:

Strongyloides

stercolaris.

2. Trichirosis :

Trichirella

spiralis.

1.Whip worm:

Trichuris

trichuria

2. Pin worm:

Enterobius

vermicularis

3. Hook worm:

Nectar

Americans

&Anclystoma

duodenale.

4. Round worm:

Ascaris

lumbercoids.

Spectrum

Fever, malaise

rash &

Arthralgia→

antihistamines

& steroids are

given to ↓

symptoms.

Mazotti- like

reactions

(headache,

dizziness,

somnolence &

hypotension)

1. N, V &

Anorexia.

2. Stephen

Johnson

syndrome.

3. Many

fatalities.

S.E

1. Meningitis:

can cross BBB.

2. Pregnancy

In pregnancy:→

embryotoxic &

teratogenic

C.I

30

Absorbed orally Not absorbed

orally except

with fat meals

Notes

Praziquantel: → Trematodes for Drugs II.

influx→ contraction→ paralysis of worm. 2+: ↑ Ca*M.O.A

Schistosomasis. : 1)*Spectrum

2) Lung fluke→ paragonimiasis.

3) Liver fluke→ clonorchiasis.

4) Cestodes as cysticercosis.

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

3) Malaise 4) Anorexia

1) Pregnancy & lactation. *C.I:

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

: → Cestodes = tape worm infectionCestodes for ugsDr III.

Albendazole Niclosamide

As Mebendazole Inhibits conversion of ADP→ ATP M.O.A:

1. Cysticercosis caused by taenia

solium

2. Hydatid disease→ echinococcus

granulosis→ 3 months

*all Cestodes.

*active # segments

*not # ova

Spectrum

In pregnancy & Children<2 years. With alcohol: 1 day of Niclosamide C.I

Nematodal infection→1-3 days

therapy

A laxative is given prior to oral

administration to purge the bowel

of dead segments & so preclude

digestion & liberation of the ova

which may lead to cystericercosis.

Notes

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.

31

H. Anti- Viral Drugs:

Herpes & Cytomegalovirus Hepatic virus Respiratory

tract

Cidofovir

Foscarnet

Fomivirsen

Vidarabin

Gancyclovir

Acyclovir

Famciclovir

Valacyclovir

Penciclovir

Valganciclovir

Lamivudine

Interferon

Telbivudine

Adefovir

Entacavir

فى بيدخل لاميفودين اسمه واحد

كأنو بيدعى كمان و الناس شئون

كافير انت قاله فواحد أديفوفير

Amantadine

Rimantadine

Zanamivir

Oseltamivir

Ribavirin

I. Respiratory tract infections:

Ribavirin 2. Inhibitors of viral

uncoating:

1.Neuraminidase

inhibitors:

Rimantadine Amantadine Zanamivir Oseltamivir

*# DNA &RNA

viruses.

* # RSV

(respiratory

synctial virus) in

infants & young.

*# Hepatitis C in

combination with

interferon − b.

*Prevention & ttt # influenza A

only.

*Amantadine is effective # some

cases of Parkinson's disease.

*Resistance: change in one à à of

.pts)50% of protein (occurs in 2M

*Prophylaxis & ttt of influenza

A & B.

*Prevent infection, however if

given 24-48 hrs after

infection→↓ duration &

intensity of symptoms.

Notes

Inhibits viral

mRNA capping &

block RNA

polymerase.

→ blocks 2Block matrix protein M

→ no fusion of the channels +H

viral membrane with the cell

membrane→ no endosome→ no

uncoating

*Neuraminidase→ inserted into

host cell memb.→ new virus.

Oseltamivir & Zanamivir*

(analogs of sialic acid) →

inhibit neuraminidase.

M.O.A:

*Oral & IV

*Inhalation in RSV

(aerosol).

*Absorption ↑ with

fatty meals.

*Amantadine → cross BBB.

*Rimantadine → doesn't cross

BBB

*Oseltamivir (prodrug) →

orally.

*Zanamivir→ inhaled or

intranasal.

Pharmaco-

kinetics:

*Teratogenic Teratogenic *Can be used in pregnancy

(category C).

Pregnancy

*Transient anemia

&↑↑ bilirubin.

*Both causes GIT intolerance

*Amantadine→ CNS S.E (ataxia,

insomnia & dizziness).

*Oseltamivir: →GIT

disturbance & nausea.

*Zanamivir: → not given to

asthmatic & COPD

S.E:

32

*Rimantadine→ fewer CNS S.E as

it doesn't cross BBB

is tricyclic amine. AmantadineN.B:

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

(Taken IV or orally & Ribavirin] + -[INF -Interferon Chronic HCV (hepatitis C virus):*

S.E: transient anemia with elevated bilirubin).

N.B: Patients with AIDS &hepatitis B are weak responders to interferon.

: Induction of host cell enzymes→ degradation of viral mRNA & *M.O.A

inhibit RNA translation. tRNA →

so taken IV, S.C or intralesionally (not glycoprotein: it is *Administration

orally).

→ once 1/2)duration (t→ prolongs form pegylated*Interferon+ PEG→

weekly dosing.

b is approved for: −*Interferon

1) Hepatitis B&C.

2)Condylomata acuminata

3)Cancers as hairy cell leukemia & Kaposi's sarcoma

A. Interferon:

HIVDNA polymerase & HBVthat is active against cytosine analogue*It is a

reverse transcriptase.

(9 hours) 1/2*orally→ t

*must be phosphorylated to triphosphate form

B. Lamivudine

:(3TC)

*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.

C. Adefovir

:dipivoxil

*Entecavir is a guanosine analogue

*Inhibits hepatitis B polymerase, preventing viral DNA synthesis.

*Once daily.

*# Lamivudine resistant HBV

*Discontinuation leads to ↑↑ hepatitis

D. Entecavir

triphosphate

*A thymidine analogue

*Inhibits hepatitis B polymerase, preventing viral DNA synthesis.

*Once daily

E. Telbivudine

triphosphate

33

Infections: Virus Herpes III.

1. Herpes simplex virus

: watery blisters on skin & mucous membranes sores Cold

especially lips

HSV-1:

Genital warts HSV-2:

infection at dorsal root ganglia. Shingles:

1. Vesicular eruption. Characterized by:

2. Neurologic pain in the

dermatome of the affected root ganglia.

2. Varicella zoster virus

(VZV):

in immunocompromised patients retinitisCauses 3. Cytomegalo virus (CMV):

A herpes virus which is the etiology agent of mononucleosis

(increase number of Monocytes)

4. Episten barr virus (EB

virus)

"Lysteria monocytogens:

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.

*#HSV1, HSV2 , VZV & EB.

*Most common use for genital infections.

*D.O.C for HSV encephalitis : IV 10 mg/kg every 8 hours. SE: oral→ nausea, vomiting&headache

Topical→ local irritation

1. Acyclovir:

*Taken: oral, IV &

topical

*Volyl ester of acyclovir→ valacyclovir→ >oral bioavailability than

acyclovir.

*↑↑ doses of valacyclovir→ Thrombotic thrombocytopenia purpura in

pts with AIDS

2.Valacyclovir:

*only#CMV induced retinitis in immunocompromised pts.

*8-20x > effective than acyclovir#CMV

3.Ganciclovir:

*IV only.

34

→↑ when combined with zidovudine, azathioprineNeutropenia:1) SE*

& mycophenolate → black box warning.

(common). fever& Photosensetivity2)

3)carcinogenic, teratogenic & embryotoxic.

Higher oral bioavailability than ganciclovir 4. Valgancyclovir

*#HSV1 &2 &VZV.

30x acyclovir->201/2*Only topical *t

: is a prodrug for the active agent penciclovir which can FamciclovirN.B:

be used orally #VZV.

S.E: Adenocarcinoma & testicular toxicity.

5. Penciclovir:

B. Others:

*#CMV induced retinitis in AIDs patients

*SE: Nephrotoxic Co-adminstered with probencid to ↓ nerotoxicity

1. Cidofovir:

IV & Intravitreal (eye

vitrious humor)

*Reversibly inhibit RNA polymerase.

*#CMV induced retinitis & acyclovir resistant HSV & VZV.

, anemia, nausea & fever.NephrotoxicityS.E: 1)

with divalent ions Chelation→ pyrophosphateIt is 2)

→hypocalcemia & hypomagnesemia.

.seizures& Arrhythmia3)

2. Foscarnet:

IV (not oral)

*Available only as ophthalmic ointment for ttt of herpetic keratitis (=keratitis

formed by HSV), It has been replaced by acyclovir which is more effective &

safer.

*Slow IV infusion for ttt of H. simplex encephalitis.

3. Vidarabine

(Ara-A):

*# CMV induced retinitis →used if other therapies failed.

S.E: Iritis, vitritis & changes in vision.

4. Fomiversin:

Intravitreal

D.O.C in HSV keratoconjunctivitis 5. Trifluridine:

Eye solution

*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.

6. Idoxuridine:

35

IV. HIV Infections: AIDS.

it is an RNA virus. :HIV*

vurion aturemassembly polyprot. comp. protease polyprot. precursor Viral DNA .rev RNA

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.

must be used in combination (highly active antiretroviral therapy) )Drugs: 1Treatment*

2) Therapy must be continued for lifelong because they are virastatic. :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.

36

Additional monitoring will depend on the antiretrovirals chosen and their potential adverse

effects.

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

ابوه يزل امتى نقول ساعتها و لاميفودين دين حيطلع ديدا لحسن اصطفوا و زيدوا

hydroxyl group. -All lack 3 : 1)General characteristics

2) They are inactive until phosphorylated by human kinases into active

triphosphate metabolite.

3) All require dosage adjustment in renal insufficiency except Abacavir.

4) All agents have black box warning concerning potential for development of

with steatosis. & hepatomegalypancreatitis, neuropathy, liver toxicity Lactic acidosis,

*Approved for children & adults→ prevents prenatal infection in

pregnancy.

*penetrates BBB.

bone marrow suppression→ so Erythropoietin is used (adjunct): *S.E

: *CI

→ ↓ glucuronidation →↑ acetaminophen& Indomethacin, Probencid1)

AZT toxicity

are activated by same pathway→ so not given Ribavirin& Stavudine2)

with AZT.

1. Zidovudine

(azidothymidine/AZT

Or Retrovir):

*crosses BBB S.E: neuropathy, lipoatrophy & hyperlipidemia 2. Stavudine (d4T):

*Crosses BBB but< AZT *taken on fasting state due to acid liability

*major SE: pancreatitis & neuropathy→ not taken with Stavudine

3.Didanosine (ddI):

*Taken with meals→↑ bioavailability.

→ once daily. S.E: GIT disturbances.1/2*Long t

CI: 1)↑ Conc. of Didanosine

2) ↓ conc. of Atazanavir→ so ritonavir is added.

4. Tenofovir (TDF):

*Used in comb. with Zidovudine for HIV.

*Used in HBV

5. Lamivudine (3TC):

*fluro derivative of Lamivudine (at least as effective as Lamivudine).

*no interactions with other drugs. 1/2t*Long

):1) hyperpigmentation of soles & palms.S.E (common*

2) Hepatomegaly & liver toxicity.

6. Emtricitabine

(FTC):

Removed from the market due to severe toxicity. 7. Zalcitabine

S.E: 1) GIT disturbances.

2) Hypersensitivity Rx→ in 5% of pts.

8. Abacavir (ABC):

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

*Adv: 1) Selective non competitive inhibitors.

2) They don't require activation by Kinase enzyme.

3) They lack effect on host cell mitochondria (i.e. no myelosupression).

4) They lack cross resistance with NRTI.

37

*Due to hepatotoxicity→ shouldn't be used in women CD4+ T-cell

.3& in men > 400 cells/mm 3counts>250 cell/mm

*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.

1. Nevirapine (Nvp):

*cyp450 inhibitor *SE: rash (most common). 2. Delaviridine (DLv):

*preferred NNRTIs by the guidelines *Bioavailability↑ by food

*cyp450 inducer *SE: Vivid dreams, dizziness & rash (25% of pts)

*Teratogenic→ CI in pregnancy

3. Efavirenz (EFv):

=40hrs→once/day1/2[t

C. Protease Inhibitors (pIs):→ avir

Ritonavir Saquinavir Indinavir Nelfinavir Fosamprenavir

Lopinavir Atazanavir Tipranavir Darunavir

داره في يعد و تيبرا اجازة ياخد نقله و لوب نديله حسام علي نلف تعالي قالتله و هندي لواحد صك ادت ريتا

*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

*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.

1. Ritonavir:

*used in combination with Ritonavir.

9hrs→ multiple dosing. *Fat meals→↑ absorption.-7 1/2*t

*Soft gelatin capsules→ to ↑ oral bioavailability as it has lowest bioavailability of

all PIs (4%).

2. Saquinavir:

1.8hrs. *Gastric acidity is necessary for absorption (fat meals↓ /2 *shortest t

abs.)

*Adequate hydration is important (1.5 L/day) → ↓ formation of kidney stones.

*Causes Hyperbilirubinemia.

3. Indinavir:

: 5 hrs. 1/2*t

*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.

4. Nelfinavir:

→ twice daily. *Ritonavir↑ plasma conc. & ↓ total daily dose.1/2*long t

cross sensitivity with other sulfa → sulfonamide→Amprenavir*Prodrug→

drugs.

:The formulation contains*

1. Vit E so avoid other Vit E supplements.

2. Propylene glycol→↑ amount causes toxicity so CI in some patients

5. Fosamprenavir

*Given with Ritonavir in one formulation……why?

2. Poor bioavailability. 1/2Because 1. Lopinavir→ short t

N.B: 1.The formulation has 4:1 ratio of Lopinavir to Ritonavir.

2. Taken twice daily.

6. Lopinavir:

38

3. The solution contains 42% alcohol so may cause disulfiram-like action

with Metronidazole.

*the only once daily combination with Ritonavir. *Food ↑ absorption.

*Prolongs PR value & ↓ HR.

blockers→ dose spacing 12 hours. 2*CI with PPIs & H

*S.E: jaundice

7. Atazanavir:

* Useful in salvage regimens in pts resistant to multidrug regimens.

* Black box warning: 1. Severe & fatal hepatitis.

2. ↑↑ intracranial hemorrhage.

8. Tipranavir:

Useful in salvage regimens 9. Darunavir:

*PIs are approved for use in pediatrics.

D. Fusion Inhibitors (Entry inhibitors):

*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].

2. Hypersensitivity reaction [erythema]

3. Pneumonia.

1. Enfuvirtide:

expressing virus.-receptor for fusion)-(co5 r CCR*Fo

*Absorbed orally.

2. Maraviroc:

E. Integrase inhibitor:

*M.O.A: Inhibits HIV integrase, which prevents viral replication by

stopping insertion of viral DNA into the host DNA.

*Twice daily

*as Enfuvirtide.

Raltegravir

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

*Category B in pregnancy.

*Well tolerated with fewer CNS S.E.

39