DRUG GROUPS...

Inhibitors of Cell Wall Synthesis



PENICILLINS
Structure

• All based on the penicillin nucleus (beta-lactam ring)
  
• Chemical synthesis or chemical modification of compounds produced by bulk fermentation of Penicillium moulds
  

Mechanism

• Inhibit formation of peptidoglycan component of the bacterial cell wall
  
• Dividing cells swell osmotically and rupture i.e. bacteriocidal against dividing cells
  
• Resistance conferred by bacterial production of a beta-lactamase which hydrolyses the beta-lactam ring
  

Adverse effects

• Generally well tolerated
  
• Occasional diarrhoea
  
• Allergic reactions including anaphylaxis occur (10% cross reactivity with cephalosporins)
  

Note

• benzylpenicillin cannot be given orally due to hydrolysis by gastric acid
  
• penicillins generally excreted by the kidney (by probenecid-sensitive organic acid transporter)
  
• IV terminal half-life generally short (<2hrs)*
  

* hence
high peak level (cidal levels) then rapid clearance to low level of
antibiotic to minimise emergence of resistance. e.g. benzylpenicillin
(pen G) IV and phenoxymethylpenicillin (pen V) PO.
Narrow spectrum i.e. gram-positive cocci, gram-positive bacilli & gram-negative cocci
Note

• Fully sensitive to penicillinases (all staph should be assumed to be resistant)
  
• Also useful for some spirochaetal infections e.g. leptospirosis and syphilis
  
• Benzylpenicillin is more active than phenoxymethylpen (i.e. not ***************alent potency)
  

Antistaphylococcal penicillins (-CLOXACILLINS)
e.g. flucloxacillin (Methicillin belongs to this class but it is no longer used clinically; laboratory resistance denotes MRSA status)
Mechanism

• Possession of acyl side-chain prevents hydrolysis (of beta-lactam bond)
  

Adverse effects

• cholestatic jaundice
  
• allergic reactions
  

Notes

• Generally
  less active (10-20 times versus benzylpen) against penicillin-sensitive
  non-staph organisms, thus if mixed infection should use in combination
  with benzylpenicillin.
  

Broad spectrum penicillins e.g. Ampicillin* and amoxycillin.
* pivampicillin is a precursor that is converted in the gut
Mechanisms
chemical modification confers:

• Activity against gram negative bacilli e.g. haemophilus influenzae and coliforms
  
• Increased activity against enterococcus (strep.) faecalis
  
• Still degraded by penicillinases
  

Adverse effects

• Ampicillin commonly causes diarrhoea
  
• Ampicillin rash frequent (if not diagnostic) in glandular fever
  
• Allergic reactions
  

Note

• Augmentin is a combination of amoxycillin plus clavulanic acid (penicillinase inhibitor)
  

<blockquote> - active against penicillinase producing staphylococci, E. coli and H. influenzae</blockquote>
<blockquote> - clavulanic acid is itself associated with diarrhoea and jaundice</blockquote>

• Mecillinam is closely related to the broad-spectrum penicillins but has a very different spectrum of activity
  

<blockquote>- active against gram negatives inc penicillinase producing enterobacteriae
</blockquote><blockquote>- no activity against gram positives or pseudomonas</blockquote><blockquote>- specialist use only</blockquote>

• Anti-pseudomonal penicillins
  e.g. piperacillin, azlocillin, ticarcillin, carbenicillin
  

Notes

• Expensive agents for specialised use only
  
• Against non-pseudomonads similar spectrum to ampicillin but less effective
  
• Useful for gram-negative infections especially with pseudomonas
  
• Rashes are common
  

Timentin is ticarcillin plus clavulanic acid
Tazocin is piperacillin plus clavulanic acid

flucloxacillin + amoxycillin : flucamox - flumox .
amoxycillin : amixillin - wafraxil - tauxil - amoxydar ....
amoxycillin + clavulanic acid : augmentin - amoclan - clavox - clamoxe - julmentin - moxiclav - fleming ...
amoxycillin + cloxacillin : amilox - wafraclox ...

cephalosporins

The cephalosporins are a valuable group of drugs that are effective in the treatment of almost all of the strains of bacteria affected by the penicillins, as well as some strains of bacteria that have become resistant to penicillin. The cephalosporins are structurally and chemically related to penicillin.
they r divided to 1st, 2nd and 3rd generations according to the sensitivity of gram bacteria to the antibiotic this means:
in case of gram -ve bacteria 3rd>2nd>1st but
in case of gram +ve bacteria 3rd<2nd<1st

ACTIONS:
Cephalosporins affect the bacterial cell wall, making it defective and unstable. This action is similar to the action of penicillin. The cephalosporins are usually bactericidal (capable of destroying bacteria)

Uses:
Treatment of susceptible microorganisms like: streptococci, staphyllococci, citrobacter, gonococci and shigella
they r used in cases of:Pharyngitis, tonsillitis, otitis media, lower respiratory infections, urinary tract infections, septicemia, and gonorrhea

Adverse reactions
1- gastrointestenal disorders like nausea, vomiting and diarrhea "most common"
2- allergic reaction may also occur "less common" and Because of the close relation of the cephalosporins to penicillin, a patient allergic to penicillin also may be allergic to the cephalosporins.
3- more serious hypersensitivity may occur which called Stevens Johnson syndrome (fever, cough, muscular aches and pains, headache, and the appearance of lesions on the skin, mucous membranes, and eyes)
4- aplastic anemia "deficiency of RBCs production"
5- finally epidermal necrolysis "death of the epidermal layer of the skin"


Contra indecations:
ALLERGY to cephalosporins and a sensitivity test must be done be4 adminstration if the patient wz a history of allergic reaction from cephalosporins or even penicillins



precautions:
MUST BE GIVEN WZ CAUTION TO PATIENTS WZ RENAL OR HEPATIC IMPAIRMENT AND IN PATIENT WZ BLEEDING DISORDERS
THIS DRUGS R PREGNANCY CATEGORY B



Interactions:
the nephrotoxicity increase when given wz the aminoglycosides "inculdes: amikin(amikacin), garamycin(gentamycin) and kanamycin (cant find trade name)

examples of cephalosporins:
1st generation:
cefadroxil"Ibidroxil, droxil"
cephalexin"amilexin, flexin"
cefazolin "cant find trade name"
cefradine " velocef "
2nd generation:
cefaclor"cloracef,medocef,fortecef"
cefprozil"cant find trade name"
3nd generation:
cefixime "magnacef , suprax ,betixim , cefix "
cefpodoxime " cefodox , podoxim "
ceftriaxone " samixon , triaxon , oncef , rosifine ,rozifine
4th generation:
cefepime"cant find trade name"

FLUOROQUINOLONES

Action:
The fluoroquinolones exert their bactericidal (bacteria-destroying) effect by interfering with an enzyme (DNA gyrase) needed by bacteria for the synthesis of DNA, This interference prevents cell reproduction, leading to death of the bacteria.

Uses:
They r effective in the treatment of gram -ve and gram +ve bacteria so that they have a wide range of action, they r used mainly in the treatment of lower resiratory tract infections, sexually transmitted infections, urinary tract infections also they r usefull in the infections of the skin...
some of them like ciprofloxacin and ofloxacin are used as opthalmic drs in the infection of the eye!!!

Adverse reactions:
fungal or bacterial superinfections!!! "pseudemembranous colitis"
nausea, diarehhea, headache, abdominal pain and dizziness.
hyper senetivity reactions may also occur!!

Contraindecation:
1- pregnant. "category C"
2- patients yonger than 18 years old (retard bune growth in rat ) which may not be like with human. and this days some studies are under investigation .


Precautions:
used in caution wz patient wz history of renal impairment or history of seizures!!
may cause photosenstivity...

Interactions:
1- they INCREASE the activity of THEOPHYLLINE
2- CIMETIDNE interfer wz the elimenation of fluroquinolons cause INCRESE in thier activity

examples:
ciprofloxacin "bactiflox,ciprolon,ciprodar amiciprox,proxal,ciprolet,ciproqin,wafrafoxacin ciprobid,microflox...."
ofloxacin "oflox,oflin"
norfloxacin"norilex ,yesnorf,..."
levofloxacin "

Macrolide


The macrolides are a group of (typically ) whose activity stems from the presence of a macrolide ring, a large ring to which one or more , usually and , are attached. The lactone ring can be either 14, 15 or 16-membered. Macrolides belong to the class of . A recent British Medical Journal article (2006? ) highlights that the combination of macrolides and (used for lowering cholesterol) is not advisable and can lead to debilitating . Warnings can be seen in the British National Formulary. This is because macrolides are potent inhibitors of the CYP450 system, particular inhibition of CYP3A4. Macrolides also have a class effect of QT prolongation.


Commonly prescribed Macrolides

erythromycin "erotab ,amithrocin,erythrosol"...
azithromycin "zomax,zocin,azitrolid,azrolid,azitam,azifast,azionce,zycin,azomyne,zithrokan"...
clarithromycin "clarix,claryl,klarimix,claritop...
spiramycin "unispira,rovac...


Uses

Macrolides are used to treat infections such as respiratory tract infections and soft tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of , and therefore macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic , , and are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against , , some and

.

Mechanism of action

The mechanism of action of the macrolides is inhibition of bacterial by binding reversibly to the subunit 50S of the bacterial , thereby inhibiting trans************************ of peptidyl-t. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within , and are therefore actually transported into the site of infection.
.

Resistance

The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either -mediated or chromosomal, i.e through mutation, and results in cross-resistance to macrolides, , and (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases) as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.


please add postreply here https://oiupharmacy.yoo7.com/montada-f1/topic-t531.htm

AMINOGLYCOSIDES

ACTIONS
The aminoglycosides exert their bactericidal effect by blocking a step in protein synthesis necessary for bacterial multiplication. They disrupt the functional ability of the bacterial cell membrane causing
cell death

USES
Mainly used in the treatment of GRAM -VE BACTERIA...
Used also against the gastrointestinal bacteria due to its poor absorption form the stomach

ADVERSE REACTIONS
1- OTOTOXICITY "damage to the organs of hearing by toxic substances" which appear as tinnitus, dizziness, vertigo , roaring in the ears and may cause loss of hearing
2- NEPHROTOXICITY "damage to the kidney" which appear as proteinuria "protien in urine", hematuria "blood in urine", decrease in urine output and increse in serum creatinine concentration. but this nephrotoxicity is usually reversible once the drug discontinued.
3- NEUROTOXICITY "damage to nervous system" which includes numbness, skin tingling, tremors, muscle twitching, convulsions and prepheral parathesia
4- they also cause nausea, vomiting, anorexia and rash

CONTRAINDICATIONS
1- pregnancy "category C and D" or lactation
2- parkinsonism or hearing problems patients

PRECAUTIONS
used cautiously in patients with renal failure (dosage adjustments may be necessary), in the elderly and in patients with neuromuscular disorders.

INTERACTIONS
1- CEPHALOSPORINS INCREASE THE NEPHROTOXICITY OF AMINOGLYCOSIDES
2- LOOP DIURETICS INCREASE THE OTOTOXICITY OF AMINOGLYCOSIDES

EXAMPLES
amikacin , gentamicin , kanamycin ,
neomycin and tobramycin "tobrex drps"

LINCOSAMIDES
another group of anti-infectives, which because of their high potential for toxicity, the lincosamides are usually used only for the treatment of serious infections in which penicillin or erythromycin (a macrolide) is not effective

ACTIONS
inhibit protien synthesis cause bacterial death

USES
These antibiotics are effective in the treatment of infections caused by a wide range of gram -ve and gram +ve microorganisms.

ADVERSE REACTIONS
1- Abdominal pain, esophagitis, nausea, vomiting, diarrhea, skin rash, and blood dyscrasias
2- These drugs also can cause pseudomembranous colitis

CONTRAINDICATIONS
1- hypersensitivity to the lincosamides
2- lactation and infancy

PRECAUTIONS
1- patients with a history of GASTROINTESTINAL disorders, RENAL disease or LIVER impairment
2- poses a danger to patients with myasthenia gravis (an autoimmune disease manifested by
extreme weakness and exhaustion of the muscles) due to thier neuromuscular blocking action

INTERACTIONS
kaolin and aluminum decrease the absorption of lincosamide

EXAMPLES
clindamycin clindam,clinimycin-T,dalamycin,clindacin-T...
lincomycin "lincocin...

CHLORAMPHENICOL

ACTIONS
inhibit protien synthesis

ADVERSE REACTIONS
1- fatal blood dyscrasias(pathologic condition of blood; disorder of cellular elements of blood)
2- nausea, vomiting and headache

CONTRAINDICATIONS
1- pregnancy or lactation "category C"
2- new born
3- G6PD "glucose 6-phosphate dehydrogenase" deficiency

PRECAUTIONS
liver or kidney diseases and geriatric patients

INTERACTION
1- chloramephenicol INCREASE the action of ORAL HYPOGLYCEMIC. ANTICOAGULANT, PHENYTOIN
2- PHENOBARBITAL DECREASE blood level of chloramephinecol

EXAMPLES
spersanechol "eye dps and eye oint", phenicol,otochol,miphenicol and spicitin tab .

LINEZOLID

ACTIONS
acts by binding to a site on a specific ribosomal RNA and preventing the formation of a component necessary for the bacteria to replicate

USES
bacteriostatic "staph" and bacteriocidial "streptococcus"
*treatment of vancomycin-resistant enterococcus

ADVERSE REACTIONS
1- nausea, vomiting, diarrhea, headache, and insomnia
2- fatigue, depression, nervousness and photosensitivity
3- membranous colitis "bacterial and fungal superinfection" and thrombocytopenia

CONTRAINDICATIONS
1- pregnancy (Category C) and lactation
2- phenylketonuria

PRECAUTIONS
used cautiously in patients with bone marrow depression, hepatic dysfunction, renal impairment, hypertension and hyperthyroidism.

INTERACTIONS
1- INCREASE the anti platlet action of ASPIRIN "thrombocytopenia"
2- DECREASE the antidepressant action of MAOIs "MonoAmine Oxidase Inhibitors" as phenelzine "

EXAMPLES
Zyvox "pfizer"

MEROPENEM

is a sterile, pyrogen-free, synthetic, broad spectrum, carbapenem antibiotic for intravenous administration
Meropenem is a broad-spectrum carbapenem antibiotic
It is active against Gram-positive and Gram-negative bacteria

Mechanism of Action
The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding- protein (PBP) targets

INDICATION
To reduce the development of drug-resistant bacteria and maintain
the effectiveness of meropenem I.V. and other antibacterial drugs, meropenem I.V.
should only be used to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria

DOSAGE AND ADMINISTRATION
The recommended dose of meropenem I.V. is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. meropenem I.V. should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes

SIDE EFFECTS
Inflammation at the injection site 2.4% Injection site reaction 0.9% Phlebitis/thrombophlebitis 0.8% Pain at the injection site 0.4% Edema at the injection site 0.2%
Systemic adverse clinical reactions that were reported irrespective of the relationship to MERREM I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus - 1.2%
pain, abdominal pain, heart failure, heart arrest, tachycardia, hypertensionoral moniliasis, anorexia, cholestatic jaundice/jaundiceanemia,peripheral edema, hypoxiainsomniarespiratory disorderurticaria, sweating

DRUG INTERACTIONS
Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended.
There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels therapeutic range considered to be 50 to 100 µg/mL total valproate

CONTRAINDICATIONS
contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have
demonstrated anaphylactic reactions to b-lactams

TRADE NAME
Merrem I.V

VANCOMYCIN

ACTIONS
acts against susceptible gram +ve bacteria by inhibiting bacterial cell wall synthesis and increasing cell wall permeability

USES
used in the treatment of serious gram-positive infections that do not respond to treatment with other anti-infectives. It also may be used in treating anti-infective–associated pseudomembranous colitis

ADVERSE REACTIONS
1- Nephrotoxicity (damage to the kidneys)
2- ototoxicity (damage to the organs of hearing)
3- nausea, chills, fever, urticaria, sudden fall in blood pressure with parenteral administration, and skin rashes

CONTRAINDICATIONS
pregnancy (Category C) and lactation.

PRECAUTIONS
used with caution in patients with renal or hearing impairment

INTERACTIONS
When administered with other ototoxic and nephrotoxic drugs, additive effects may be seen.

EXAMPLES
vancomycin, vancolon "vials"

spectinomycin

What is spectinomycin?
Spectinomycin is an antibiotic. It fights bacteria in the body.
Spectinomycin is used in the treatment of gonorrhea.
Spectinomycin may also be used for purposes other than those listed here.

What should I discuss with my health care provider before taking spectinomycin?


Do not take spectinomycin without first talking to your doctor if you have had an allergic reaction to it in the past.
Before taking spectinomycin, talk to your doctor if you have liver or or other serious medical problems. You may not be able to use spectinomycin, or you may require a dosage adjustment or special monitoring during treatment.
Spectinomycin is in the FDA pregnancy category B. This means that it is not expected to be harmful to an unborn baby. Do not use spectinomycin without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether spectinomycin passes into breast milk. Do not take spectinomycin without first talking to your doctor if you are breast-feeding a baby.

How should I take spectinomycin?

Spectinomycin will be administered as an injection by a healthcare provider.

What happens if I miss a dose?

Since spectinomycin is usually administered as a single injection, missing dose is not likely to occur.

What should I avoid while taking spectinomycin?
There are no restrictions on food, beverages, or activities during treatment with spectinomycin unless otherwise directed by your doctor.

What are the possible side effects of spectinomycin?
If you experience a rare but serious allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives), stop taking spectinomycin and seek emergency medical attention.
Other less serious side effects may be more likely to occur. Continue to use spectinomycin and talk to your doctor if you experience:
nausea;
soreness at the injection site; or
fever.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

LEPROSY

Leprosy is a chronic, communicable disease spread by prolonged, intimate contact with an infected person. Peripheral nerves are affected, and skin involvement is present. Lesions may be confined to a few isolated areas or may be fairly widespread over the entire body.
Leprosy also referred to as Hansen’s disease, is caused by the bacterium Mycobacterium leprae.

LEPROSTATIC DRUGS
1- Clofazimine

ACTIONS
Clofazimine is primarily bactericidal against M. leprae. The exact mode of action of this drug is unknown

ADVERSE REACTIONS
pigmentation of the skin, abdominal pain, diarrhea, nausea, and vomiting.

CONTRAINDICATIONS
pregnancy and lactation "category C"
"may lead to pigmented baby if taken during pregnancy"

PRECAUTIONS
used cautiously in patients with gastrointestinal disorders especially diarrhea

INTERACTIONS
no significant

EXAMPLES
Lamprene "Novartis" (not in sudan )


2- Dapsone

ACTIONS
bactericidal and bacteriostatic against M. leprae.

USES
1- leprosy
2- dermatitis herpetiformis "a chronic, inflammatory skin disease"

ADVERSE REACTIONS
1- hemolysis "destruction of red blood cells"
2- nausea, vomiting, anorexia, and blurred vision.

CONTRAINDICATIONS
1- pregnancy "category C" and lactation "cause hemolysis to baby"
2- anemia

PRECAUTIONS
used with caution in patients with severe cardiopulmonary disease and hepatic dysfunction

INTERACTIONS
no significant

EXAMPLES
Dapsone

Antiviral Drugs

Historically, the discovery of antiviral drugs has been largely fortuitous. Spurred on by success with antibiotics, drug companies launched huge blind-screening programmes - with relatively little success. Lead compounds were modified by chemists in an attempt to improve bioactivity. Solubility, stability, availability and activity are all important
Scientists would like to think rationale drug design could be accomplished i.e determine the structure of your target in a complex with a known inhibitor. Use this and other biochemical knowledge to "theoretically design" a better inhibitor. Make it and test it.
However in recent years combinatorial chemistry has become fashionable.This uses robotic techniques to make enormous numbers of different compounds from a limited number of subunits. The nature of the subunits can vary widely. Consider a library of 10 compounds. One reaction will give 100 different compounds.
1-1....1-10; 2-1...2-10; .....; 10-1....10-10. Two reactions will give 1000. Ten reactions will give one hundred thousand million!

The individual compounds, or pools of compunds are then assayed for bioactivity. Any active compounds identified can be used as a lead compound.
The key to success in drug development is specificity, e.g. Paul Erlich's "magic bullets". Any stage of virus replication can be a target for a drug, but drug must be more toxic to virus than to the host.


CHEMOTHERAPEUTIC INDEX

Dose of drug which inhibits virus replication / Dose of drug which is toxic to host

The smaller this value of this number the better, i.e. several orders of magnitude difference is required for a really safe drug.
Modern technology allows deliberate design of drugs, but to do this, need to "know your enemy":

*
Molecular biology - understanding viral replication and producing specific targets for inhibition
*
Computer aided design (C.A.D.)

Strategies for antiviral therapy

Commonly used therapuetically. ASAP after infection or clinical signs of infection. Prophylactic use occasionally. Any of the stages of viral replication can be a target for antiviral intervention. The only requirements are:

1.
That the process targeted be essential for virus replication.
2.
That the theraputic agent is active against the virus while having "acceptable toxicity" to the host organism

Attachment

This phase of replication can be inhibited in two ways:

a) Using agents which mimic the V.A.P. and bind to the cellular receptor, e.g:

*
anti-receptor antibodies
*
V.A.P. anti-idiotypic antibodies
*
natural ligands of the receptor, e.g. epidermal growth factor/Vaccinia virus
*
synthetic ligands, e.g. synthetic peptides resembling the receptor-binding domain of the V.A.P. itself.




b) Agents which mimic the receptor and bind to the V.A.P:

*
anti-V.A.P. antibodies (a natural component of the antibody response to virus infection/vaccination)
*
receptor anti-idiotypic antibodies
*
extraneous receptor, e.g. rsCD4/HIV
*
synthetic receptor mimics, e.g. sialic acid derivatives/influenza virus.




While the above are promising lines of experimental research, there are considerable problems with clinical use of any of these substances. The cost of synthetic peptides is prohibitive when the amounts required for clinically effective whole body doses; the generation of anti-idiotypic antibodies is a complex, poorly understood process; the pharmacokinetics of many of these synthetic compounds is very poor.

Penetration / Uncoating

It is difficult to specifically target these stages of the life cycle as relatively little is known about them. Uncoating in particular is largely mediated by cellular enzymes, although like penetration, is often influenced by one or more virus proteins.

Pleconaril
is a broad spectrum anti-picorna virus agent. It is orally bioavailable and reduces peak viral titres by more than 99%; symptoms are improved. It is a small cyclic drug which binds to a canyon pore of the virus. In doing so it blocks attachment and uncoating of the viral particle

Amantadine and rimantadine
are active against influenza A viruses. The action of these closely related agents is complex and incompletely understood, but they are believed to block cellular membrane ion channels.

*
The target for both drugs is the matrix protein (M2).
*
Drug-treated cells are unable to lower the pH of the endosomal compartment (a function normally controlled by the M2 gene product), a process which is essential to induce conformational changes in the HA protein to permit membrane fusion.





Genome Replication

Many viruses have evolved their own specific enzymatic mechanisms to preferentially replicate virus nucleic acids at the expense of cellular molecules. There is often sufficient specificity in virus polymerases to provide a target for a specific antiviral agent, and this method has produced the majority of the specific antiviral drugs currently in use.
The majority of these drugs function as polymerase substrate (i.e. nucleoside/nucleotide) analogues. The toxicity of these drugs varies considerably from some which are well tolerated (e.g. acyclovir) to others which are highly toxic (e.g. IdU/TFT/AZT). There is a serious problem with the pharmacokinetics of these nucleoside analogues, e.g. typically short serum half lives of 1-4h.

Nucleoside analogues are in fact pro-drugs, since they need to be phosphorylated before becoming effective. This is the key to their selectivity:

*
Acyclovir
*
is phosphorylated by HSV tk 200 times more efficiently than by cellular enzymes. The cell DNA polymerase is less sensitive to it than the viral DNA polymerase
*
.
o
Gancyclovir
*
is 10 times more effective against CMV than acyclovir since it is specifically phosphorylated by a CMV-encoded kinase encoded by gene UL97 :




More recently, a series of other nucleoside analogues derived from these drugs and active against herpesviruses have been developed:




Nucleoside analogues active against HIV:





Gene Expression

Virus gene expression is less amenable to intervention than genome replication, since viruses are much more dependent on the cellular machinery for transcription, mRNA splicing, cytoplasmic export and translation than for replication.

Assembly / Maturation / Release

As stated above, for the majority of viruses, these processes are poorly understood. Two drugs with anti influenza activity are available, Relenza
taken as an aerosol and
Tamiflu taken as a pill. The latter is active against both A and B strains. Both function as neuraminidase inhibitors and prevent the release of budded viruses from the cell. Because they act late in the life cycle of the virus it is hoped that problems with resistance emergence will be minimised. Tamiflu is reported to be 90% effective as a prophylactic agent.

Other antiviral drugs:




Therapy of HIV Infection:

Several distinct classes of drugs are now used to treat HIV infection

Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs).
*
Zidovudine (AZT = ZDV, Retrovir) first approved in 1987
*
Didanosine (ddI, Videx)
*
Zalcitabine (ddC, Hivid)
*
Stavudine (d4T, Zerit)
*
Lamivudine (3TC, Epivir
*
)


Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs).
In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase.
*
Nevirapine (Viramune)
*
Delavirdine (Rescriptor)

Protease Inhibitors

. These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells.
*
Saquinavir (Invirase) first approved in 1995
*
Ritonavir (Norvir)
*
Indinavir (Crixivan)
*
Nelfinavir (Viracept)

Problems

Toxicity. AZT causes anaemia, in fact its toxicity is such that it was originally rejected as an anti-tumour drug! Interferon and acyclovir can cause severe nausia and vomiting. Pregnancy is an important contraindication because of possible teratogenic effects.

PARASITES

an organism that lives in or on another organism (the host)
without contributing to the survivalor well-being of the host
it includes:
1- Helminthiasis (invasion of the body by helminths [worms]
helminths includes:
- Roundworms "Ascaris"
- pinworms "Enterobius vermicularis"
- whipworms "Trichuris trichiura"
- hookworms "Ancylostoma"
- tapeworms "Taenia"
2- malaria (an infectious disease caused by a protozoan and transmitted to humans through a bite from an infected mosquito)
3- amebiasis (invasion of the body by the ameba Entamoeba histolytica) are worldwide health problems caused by parasites.


ANTIPARASITIC DRUGS
1- ANTHELMINTICS
1- ALBENDAZOLE
ACTIONS
interferes with the synthesis of the parasite’s microtubules, resulting in death of susceptible larva.

USES
used to treat larval forms of pork tapeworm and to treat liver, lung, and peritoneum
disease caused by the dog tapeworm.

ADVERSE REACTIONS
no significant

CONTRAINDICATIONS
pregnancy "category C" (cause teratogency and emberyotoxicity)

PRECAUTIONS
1- patients with hepatic impairment
2- during lactation

INTERACTION
The effects of albendazole are increased with dexamethasone and cimetidine.

EXAMPLES
albenda , zentel


2- MEBENDAZOLE
ACTIONS
Act by blocking the uptake of glucose by the helminth, resulting in a depletion of the helminth’s own glycogen. Glycogen depletion results in a decreased formation of adenosine triphosphate, which is required by the helminth for reproduction and survival.

USES
treat whipworm, pinworm, roundworm, American hookworm, and the common hookworm.

ADVERSE REACTIONS
abdominal pain and diarrhea

CONTRAINDICATIONS
pregnancy "category C" (cause teratogency and emberyotoxicity)

PRECAUTIONS
during lactation

INTERACTION
The effects of mebendazole are decreased with hydantoins and carbamazepine

EXAMPLES
vermox , anthelmin, antivir, vermin


3- PYRANTEL
ACTIONS
causes paralysis of the helmenthis causes it's excreation in feces

USES
treat roundworm and pinworm

ADVERSE REACTIONS
nausea, vomiting, abdominal cramps, or diarrhea.

CONTRAINDICATIONS
Pregnancy "category C"

PRECAUTIONS
patients with liver dysfunction, malnutrition, or anemia

INTERACTION
contraindicated with piperazine

EXAMPLES
Antiminth


4- THIABENDAZOLE
ACTION
This drug appears to suppress egg or larval production and therefore may interrupt the life cycle of the helminth

USES
treat threadworm

ADVERSE REACTIONS
drowsiness, and dizziness

CONTRAINDICATIONS
Pregnancy category C

PRECAUTIONS
patients with hepatic or renal disease

INTERACTION
thiabendazole increase xanthine action


2- ANTIMALARIAL DUGS
1- CHLOROQUINE
ACTION
interfere with, or are active against, the life cycle of the plasmodium, primarily when it is present in the red blood cells.

USES
1. Suppression—the prevention of malaria
2. Treatment—the management of a malarial attack
3. extraintestinal amebiasis
4. rheumatoid

ADVERSE REACTIONS
hypotension, visual disturbances, headache, nausea, vomiting, anorexia, diarrhea, and abdominal cramps.

CONTRAINDICATIONS
pregnancy "category C"

PRECAUTIONS
1- hepatic disease
2- bone marrow depression
3- in children

INTERACTIONS
1- increase the hepatotoxicity of other hepatotoxic drugs
2- food which acidify the urine (cranberries, plums, Disturbed Sensory Perception: prunes, meats, cheeses, eggs, fish, and grains) decrease the chloroquine action

EXAMPLE
amiquine , eliquine ( no long use in sudan )

2- DOXYCYCLINE
see tetracycline before


3- QUININE
ACTION
as chloroquine

USES
1. Suppression—the prevention of malaria
2. Treatment—the management of a malarial attack
3. prevention and treatment of nocturnal leg cramps

ADVERSE REACTIONS
1- cinchonism "group of symptoms associated with quinine, including tinnitus, dizziness, headache, gastrointestinal disturbances, and visual disturbances.
2- hematologic changes, vertigo, and skin rash.

CONTRAINDICATIONS
Pregnancy category X

PRECAUTIONS
myasthenia gravis (may cause respiratory distress and dysphagia)

INTERACTIONS
1- antacid containing aluminium decrease the absorption of quinine
2- quinine increase the action of digitalis and warfarin

EXAMPLES
quinine


3- AMEBICIDES
1- CHLOROQUINE
see it before

2- IODOQUINOL
ACTION
kill amebas

USES
treat intestinal amebiasis

ADVERSE REACTIONS
skin eruptions, nausea, vomiting, fever, chills, abdominal cramps, vertigo, and diarrhea

CONTRAINDICATIONS
during pregnancy and lactation

PRECAUTIONS
patients with thyroid disease

INTERACTIONS
no significant



3- METRONIDAZOLE
ACTION
kill amoebas

USES
1- treat intestinal amebiasis
2- treat infections caused by susceptible microorganisms

ADVERSE REACTIONS
Convulsive seizures, headache, nausea, and peripheral neuropathy (numbness and tingling of the extremities)

CONTRAINDICATION
pregnancy in the1st trimester "category B"

PRECAUTIONS
Patients with blood dyscrasias, seizure disorders, and severe hepatic impairment.
The patient must avoid alcohol while taking metronidazole.

INTERACTIONS
1- cimetidine increase the action of metronidazole
2- phenobarbital decrease the action of metronidazole
3- metronidazole increase the action of warfarin

EXAMPLES
flagyl, amrizole , metrozol , aminidazol ,cityzol ,wafrazol , marwazol , yesozol

4- PAROMOMYCIN
See aminoglycosides before

systemic antifungal drus


Definition

Systemic antifungal drugs are medicines taken by mouth or by injection to treat deep infections caused by a fungus.

Purpose

Systemic antifungal drugs are used to treat infections in various parts of the body that are caused by a fungus. A fungus is an organism that can be either one-celled or filamentous. Unlike a plant, which makes its own food, or an animal, which eats plants or other animals, a fungus survives by invading and living off other living things. Fungi thrive in moist, dark places, including some parts of the body.
Fungal infections can either be systemic, meaning that the infection is deep, or topical (dermatophytic), meaning that the infection is superficial and occurs on the skin. Additionally, yeast infections can affect the mucous membranes of the body. Fungal infections on the skin are usually treated with creams or ointments (topical antifungal drugs). However, systemic infections, yeast infections or topical infections that do not clear up after treatment with creams or ointments may need to be treated with systemic antifungal drugs. These drugs are used, for example, to treat common fungal infections such as tinea (ringworm), which occurs on the skin or candidiasis (a yeast infection, also known as trush), which can occur in the throat, in the vagina, or in other parts of the body. They are also used to treat other deep fungal infections such as histoplasmosis, blastomycosis, and aspergillosis, which can affect the lungs and other organs. They are sometimes used to prevent or treat fungal infections in people whose immune systems are weakened, such as bone marrow or organ transplant patients and people with AIDS.

Description

Antifungal drugs are categorized depending on their route or site of action, their mechanism of action and their chemical nature.
Systemic antifungal drugs, such as
capsofungin
flucytosine
fluconazole candivast , diflazol, forcan
itraconazole canditral,
ketoconazole Nizoral , ketrozol , phytoral
miconazole

Recommended dosage

The recommended dosage depends on the type of antifungal drug and the nature and extent of fungal infection being treated. Doses may also be different for different patients. The prescribing physician or the pharmacist can provide dosage information. Systemic antifungal drugs must be taken exactly as directed. Itraconazole and ketoconazole should be taken with food.
Fungal infections can take a long time to clear up, so it may be necessary to take the medication for several months, or even for a year or longer. It is very important to keep taking the medicine for as long as the physician says to take it, even if symptoms seem to improve. If the drug is stopped too soon, the symptoms may return.
Systemic antifungal drugs work best when their amount is kept constant in the body, meaning that they have to be taken regularly, at the same time every day, and without missing any doses.
Patients taking the liquid form of ketoconazole should use a specially marked medicine spoon or other medicine measuring device to make sure they take the correct amount. A regular household teaspoon may not hold the right amount of medicine. Ask the pharmacists about ways to accurately measure the dose of these drugs.

Precautions

If symptoms do not improve within a few weeks, the prescribing physician should be informed.
While taking this medicine, regular medical visits should be scheduled. The physician needs to keep checking for side effects throughout the antifungal therapy.
Some people feel drowsy or dizzy while taking systemic antifungal drugs. Anyone who takes these drugs should not drive, use machines or do anything else that might be dangerous until they have found out how the drugs affect them.
Liver problems, stomach problems and other problems may occur in people who drink alcohol while taking systemic antifungal drugs. Alcohol and prescription or nonprescription (over-the-counter) drugs that contain alcohol should be avoided while taking antifungal drugs. (Medicines that may contain alcohol include some cough syrups, tonics, and elixirs.) Alcohol should be avoided for at least a day after taking an antifungal drug.
The antifungal drug ketoconazole may make the eyes unusually sensitive to light. Wearing sunglasses and avoiding exposure to bright light may help.

Special conditions

People with certain medical conditions or who are taking certain other medicines can have problems if they take systemic antifungal drugs. Before taking these drugs, the prescribing physician should be informed about any of the following conditions:

ALLERGIES

Anyone who has had unusual reactions to systemic antifungal drugs in the past should let his or her physician know about the problem before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY

In laboratory studies of animals, systemic antifungal drugs have caused birth defects and other problems in the mother and fetus. Studies have not been done on pregnant women, so it is not known whether these drugs cause similar effects in people. Women who are pregnant or who plan to become pregnant should check with their physicians before taking systemic antifungal drugs. Any woman who becomes pregnant while taking these drugs should let her physician know immediately.

BREASTFEEDING

Systemic antifungal drugs pass into breast milk. Women who are breastfeeding should check with their physicians before using systemic antifungal drugs.

OTHER MEDICAL CONDITIONS

People who have medical conditions that deplete stomach acid (achlorhydria) or decrease stomach acid (hypochlorhydria) should be sure to inform their physicians about their condition before they use a systemic antifungal drug. These drugs are not active in their natural form, but must be converted to the active form by an acid. If these is not enough stomach acid, the drugs will be ineffective. For people with insufficient stomach acid, it may help to take the medicine with an acidic drink, such as a cola (or other can't contain bigs pepsin for Muslims ) . The patient's health care provider can suggest the best way to take the medicine.
Before using systemic antifungal drugs, people with any of these medical problems should also make sure their physicians are aware of their conditions:

*
current or past alcohol abuse
*
liver disease
*
kidney disease

USE OF CERTAIN MEDICINES

Taking systemic antifungal drugs with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Side effects
Fluconazole

Although rare, severe allergic reactions to this medicine have been reported. Call a physician immediately if any of these symptoms develop after taking fluconazole :

*
hives, itching, or swelling
*
breathing or swallowing problems
*
sudden drop in blood pressure
*
diarrhea
*
abdominal pain

Ketoconazole

Ketoconazole has caused anaphylaxis (a life-threatening allergic reaction) in some people after their first dose. This is a rare reaction.

Systemic antifungal drugs in general

Systemic antifungal drugs may cause serious and possibly life-threatening liver damage. Patients who take these drugs should have liver function tests before they start taking the medicine and as often as their physician recommends while they are taking it. The physician should be notified immediately if any of these symptoms develop:

*
loss of appetite
*
nausea or vomiting
*
yellow skin or eyes
*
unusual fatigue
*
dark urine
*
pale stools

The most common minor side effects of systemic antifungal drugs are constipation, diarrhea, nausea, vomiting, headache, drowsiness, dizziness, and flushing of the face or skin. These problems usually go away as the body adjusts to the drug and do not require medical treatment. Less common side effects, such as menstrual problems in women, breast enlargement in men, and decreased sexual ability in men also may occur and do not need medical attention unless they do not improve in a reasonable amount of time.
More serious side effects are not common, but may occur. If any of the following side effects occur, check with the physician who prescribed the medicine immediately:

*
fever and chills
*
skin rash or itching
*
high blood pressure
*
pain, redness, or swelling at site of injection (for injectable miconazole)

Other rare side effects are possible. Anyone who has unusual symptoms after taking systemic antifungal drugs should get in touch with his or her physician.

Interactions

Serious and possibly life-threatening side effects can result if the oral forms of itraconazole or ketoconazole or the injectable form of miconazole are taken with certain drugs. Do not take those types of systemic antifungal drugs with any of the following drugs unless the physician approves of the therapy:

*
astemizole
*
cisapride
*
antacids
*
theophylline-containing anti-wheezing medications

Taking an acid blocker such as cimetidine (Tagamet), famotidine (febcid), nizatidine , omeprazole (gasec), or ranitidine (Zantac) at the same time as a systemic antifungal drug may prevent the antifungal drug from working properly. For best results, take the acid blocker at least 2 hours after taking the antifungal drug.
In addition, systemic antifungal drugs may interact with many other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Anyone who takes systemic antifungal drugs should inform the prescribing physician about all other prescription and nonprescription (over-the-counter) medicines he or she is taking. Among the drugs that may interact with systemic antifungal drugs are:

*
acetaminophen
*
birth control pills
*
male hormones (androgens)
*
female hormones (estrogens)
*
medicine for other types of infections
*
antidepressants
*
antihistamines
*
muscle relaxants
*
medicine for diabetes, such as tolbutamide , glyburide , and glipizide
*
blood-thinning medicine, such as warfarin

The list above does not include every drug that may interact with systemic antifungal drugs. Be sure to check with a physician or pharmacist before combining systemic antifungal drugs with any other medicine.

topical antifungal drugs

Definition

Topical antifungal drugs are medicines applied to the skin to treat skin infections caused by a fungus.

Purpose

Dermatologic fungal infections are usually described by their external infection on the body: tinea pedis (infection of the foot), tinea unguium (infection of the nails), tinia capitis (infection of the scalp.) Three types of fungus are involved in most skin infections: Trichophyton, Epidermophyton, and Microsporum. Mild infections are usually susceptible to topical therapy, however severe or resistant infections may require systemic treatment.

Description

There are a large number of drugs currently available in topical form for fungal infections.
miconazole daktarin , mycoheal , mikozal , Miconaz
clotrimazole candid , imidil , candi-mazol
econazole pevaryl
ketoconazole Nizoral, ketonaz , kenazol , fungipan
nystatin mycosat , nystasir , mycostatin
oxiconazole
sulconazole and the allylamine derivatives (butenafine , naftifine , terbinafine ),

the drugs in this therapeutic class are chemically distinct from each other. All drugs when applied topically have a good margin of safety, and most show a high degree of effectiveness. There are no studies comparing drugs on which to base a recommendation for drugs of choice. Although some of the topical antifungals are available over-the-counter, they may be as effective as prescription drugs for this purpose.
Traditional antifungal drugs such as undecylinic acid (Cruex, Desenex) and gentian violet (also known as crystal violet) remain available, but have a lower cure rate (complete eradication of fungus) than the newer agents and are not recommended. Tolnaftate has a lower cure rate than the newer drugs, but may be used prophylactically to prevent infection.

Recommended dosage

All drugs are applied topically. Consult individual product information for specific application recommendations.
As with all topical products, selection of the dosage form may be as important as proper drug selection. Consider factors such as presence or absence of hair on the affected area, and type of skin to which the medication is to be applied. Thin liquids may preferable for application to hairy areas, creams for the hands and face, and ointments may be preferable for the trunk and legs. Other dosage forms available include shampoos and sprays. candimazol & candid lotion are available in formulations for topical treatment of nail fungus as well as skin infections .
Most topical antifungal drugs require four weeks of treatment. Infections in some areas, particularly the spaces between toes, may take up to six weeks for cure.

Precautions

Most topical antifungal agents are well tolerated. The most common adverse effects are localized irritation caused by the vehicle or its components. This may include redness, itch, and a burning sensation. Some direct allergic reactions are possible.
Topical antifungal drugs should only be applied in accordance with labeled uses. They are not intended or ophthalmic (eye) use. Application to mucous membranes should be limited to appropriate formulations.
The antifungal drugs have not been evaluated for safety in pregnancy and lactation on topical application under the pregnancy risk category system. Although systemic absorption is probably low, review specific references. Gentian violet is labeled with a warning against use in pregnancy.

Interactions

Topical antifungal drugs have no recognized drug-drug or food-drug interactions.