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UNIT 2; Anti Microbial.pptx

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S
Shahid Khan

All Antimicrobial Drugs

Health & Medicine
1 of 345
Antimicrobial Drugs Dr. Shahid Khan, Pharm.D, RPh Lecturer, National Institute Of Health and Management Sciences (NiHMS), Peshawar
Chemotherapy
Introduction Definition: Chemotherapy is the treatment of various diseases caused by pathogenic organisms (bacteria, fungi, viruses, protozoa, worms) with chemical substances, which due to their selective toxicity, destroy or remove pathogenic organisms without injuring the host. The chemical substances used for this purpose are chemotherapeutic agents. Drugs use for treatment of cancer ( Antineoplastic drugs) are also included in chemotherapy.
History of Chemotherapy • The first drug used for cancer chemotherapy did not start out as a medicine. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. • Doctors reasoned that something that damaged the rapidly growing white blood cells might have a similar effect on cancer. So, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable.
 Discovered first cure for syphilis  Neoarsphenamine was widely used for treatment of syphilis untill1945 when penicillin superseded it
Antimicrobial Chemotherapy 1. Antibacterial Drugs: Antibiotics, Sulphonamide, Quinolone, Anti TB Drugs, Drugs for UTI etc 2. Antifungal Drugs 3. AntiViral Drugs 4. Anti Protozoal Drugs 5. Anthelmintics
Why chemotherapy is different from other treatments • Treatments like radiation and surgery are considered local treatments. They act only in one area of the body such as the breast, lung, or prostate and usually target the cancer directly. • Chemotherapy differs from surgery or radiation in that it’s almost always used as a systemic treatment. • This means the drugs travel throughout the body to reach cancer cells wherever they are.
Principle of Antimicrobial Therapy •Site of infection •Responsible organism •Sensitivity of drug Diagnosis •Acute infection require chemotherapy while chronic infection may not. •The chronic abscess respond poorly, although chemotherapy cover is essential if surgery is undertaken to avoid a flare-up of infection Decide Chemotherapy Is necessary •Specificity (spectrum of activity, antimicrobial activity of drug) •Pharmacokinetic factor •Patient related factor Select the drug
Principle of Antimicrobial Therapy • Inadequate dose may develop resistance • Intermediate dose may not cure disease • Optimize dose should be use for therapy Frequency and Duration of Drug Administration • Acute infection treated for 5-10days • But for some infections such as TB, medication continue to avoid relapse Continue Therapy • After therapy, symptoms and signs may disappear before pathogen eradicated. Test for Cure
Identification of infecting organisms • Characterizing the organism is central to selection of proper drug. • A rapid assessment can be made by gram staining which is useful in identifying presence of microorganisms in body fluids that are normally sterile ( Blood, Serum, CSF, Pleural Fluid, Peritoneal Fluid and urine). • However, it is necessary to culture infective microorganism to arrive at conclusive diagnosis. Thus it is imp to have sample prior to start treatment
Empiric Therapy prior to identification of micro organism • Ideally, antimicrobial agent used to treat an infection is select after the organism has been identified and its drug susceptibility established. However in critical cases, wait can be dangerous. So immediate empiric therapy is indicated. • Broad spectrum therapy maybe indicated initially started when organism is unknown or polymicrobial infection is likely.
Determining antimicrobial susceptibility of infective organism • After organism is cultured, its susceptibility to specific antibiotic serve as a guide in choosing antimicrobial therapy. • Some pathogens such as: Streptococcus pyogenes and Neisseria meningitis, usually have predictable susceptible pattern to certain antibiotics. • In contrast, most gram negative bacilli, enterococci and staphylococcus species often show unpredictable susceptibility to various antibiotics. Therefore require susceptibility testing to determine appropriate therapy.
Bacteriostatic Vs Bacteriocidal • Antimicrobial drugs are classified as either bacteriostatic or bactericidal. • Bacteriostatic drugs arrest the growth and replication of bacteria at serum (or urine) levels achievable in patient thus limiting spread of infection. • Bactericidal drugs kill bacteria at drug serum levels achievable in the patient. Because of their severe action they are drug of choice in seriously ill patient. • Example: Chloramphenicol is bacteriostatic against gram –ive rods, and is bactericidal against other organisms such S.pneumoniae.
MIC & MBC • MIC is minimum inhibitory concentration that is lowest concentration of antibiotic that inhibit bacterial growth. ( to provide effective therapy antibiotic conc. in body tissue and fluids should be greater than MIC) • MBC is minimum bactericidal concentration that kills the bacteria under investigation. The minimum bactericidal concentration (MBC) is lowest conc. of antimicrobial agent that kills 99.9%.
Effect of site of infection on therapy • Adequate levels of antibiotic must reach site of infection for invading micro organism. • For this points of consideration are: 1. Lipid Solubility of drug 2. Molecular weight of drug 3. Protein binding of drug
Patient Factors 1. Immune System: Elimination of infecting organism depends upon intact immune system. If weak then there will be problem 2. Renal Dysfunction: poor kidney function (10% or less of normal) causes accumulation of antibiotics that would otherwise easily eliminated. Dose adjustment needed!!! 3. Hepatic dysfunction: Antibiotics ( erythromycin and tetracycline) must use with caution. 4. Poor Perfusion: decrease circulation to anatomic areas such as lower limb, decrease the amount of antibiotic in that specific area. 5. Age: Renal/hepatic elimination processes are often poorly developed in newborns, making neonate vulnerable to toxic effects of chloramphenicol and sulfonamide. Young children should not treated with tetracycline or qunilone which affect bone growth.
6. Pregnancy: Many antibiotics cross placenta. Adverse effects are rare, except for tooth dysplasia and inhibition of bone growth encountered with tetracycline. 7. Lactation: Drug administered to a lactating mother may enter the nursing infant via breast milk. Although conc. Is low but the total dose to infant maybe sufficient to produce determental effects.
Safety of Agent • Many antibiotics such as penicillin's, are among the least toxic of all drugs because they interfere with a site unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol) are less microorganism specific and are reserved for life threatening infections because of the drug’s potential for serious toxicity to patient.
Route Of Administration • The oral route of administration is chosen for infections that are mild and is favorable for treatment on an outpatient basis. • In patients using IV in start should switch to oral agents should occur. • However, some antibiotics such as vancomycin, aminoglycosides and amphotericin B are so poorly absorbed from GIT that adequate serum levels cannot be obtained by oral administration.
Determinants of Rational Dosing • Rational dosing depends upon drug pharmacodynamics (the relationship of dug conc. to antimicrobial effects) and pharmacokinetics (ADME) • Three imp properties that have a significant influence on the frequency of dosing are: 1. Conc. Dependent killing (e.g Aminoglycoside) 2. Time Dependent killing (e.g Beta lactam) 3. Postantibiotic effect (e.g fluroquinolones)
Chemotherapeutic Spectra 1. Narrow Spectrum Antibiotics : chemotherapeutic agents acting only on a single or a limited group of micro organisms are said to have a narrow spectrum. For example, isoniazid is active only against mycobacteria. 2. Extended Spectrum Antibiotics: those antibiotics which are effective against gram positive organisms and also against a significant number of gram negative bacteria. For example, ampicillin 3. Broad Spectrum Antibiotics: drugs such as tetracycline and chloramphenicol affect a wide variety of microbes.
Combination of Antimicrobial Drugs • It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility of super infection, decrease resistance, and minimize toxicity. • For example: In tuberculosis combination of therapy is used.
Advantages & Disadvantages of combination • Advantages: certain combination of antibiotics such as beta lactam and aminoglycoside show synergism, means combination is more effective than alone. ( multiple drugs are only given in special situation when cause is unknown) • Disadvantages: A no. of antibiotics act only when micro organisms are multiplying. Thus, co administration of an agent that causes bacteriostasis plus second agent that is bactericidal may result in first interfering with the action of second. ( for example: bacteriostatic tetracycline drugs may interfere with bactericidal effect of penicillin and cephalosporin)
Drug Resistance • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. • Some organisms are inherently resistant to an antibiotic. E.g Gram-ive organisms to vancomycin • Other causes are: 1. Genetic alteration  Mutation of DNA  DNA transfer of drug resistance 2. Altered expression of proteins in drug resistant micro organisms  Modification of target sites  Decrease accumulation  Enzymatic inactivation
Prophylactic antibiotics • Antibiotics use for prevention rather than treatment. • Duration of prophylaxis should be closely observed to prevent unnecessary antibiotic exposure.
Complication of Antibiotic therapy • Hypersensitivity ( Penicillin) • Direct toxicity (aminoglycoside cause ototoxicity) • Super infections (Broad spectrum antibiotics can suppress normal flora of the upper respiratory, intestinal, and genitourinary leading to overgrowth of opportunistic organisms especially fungi which is difficult to treat)
Actions Of Antimicrobial Drugs
The Action of Antimicrobial Drugs
Cell wall Synthesis inhibitors • Some antimicrobial drugs selectively interfere with the synthesis of bacterial cell wall- a structure that mammalian cell do not posses. • The cell wall is composed of polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross links. • To be maximally effective, inhibitors of cell wall synthesis require actively proliferating micro organisms, they have little or no effect on bacteria that are not growing or dividing. • The most important member of the group are beta lactam antibiotics and vancomycin.
Penicillin
Penicillin • First antibiotic, extracted from the mould, Pencillium notatum. The penicillins are among the most widely effective and least toxic drugs known, but increase resistance has limited their use. • Member of this family differ from one and another in R substituent attached to the 6-aminopencillianic acid residue. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, cross hypersensitivity and susceptibility to bacterial degradative enzymes (ß lactamases). • Benzylpenicillin ( penicillin G) was first natural penicillin available for clinical use. Other natural penicillin are phenoxymethylpenicillin (penicillin V) and phenethicillin. • All penicillin contain Penicillin nucleus ( 6-aminopenicillinic acid) consisting of a four membered beta lactam ring fused with a thiazolidine ring. The beta lactam rings carries a secondary amino group ( R-NH) where acidic radical can be attached to amino group at –R- thereby producing large number of semi synthetic penicillins with different properties.
Penicillin
Members of Penicillin Penicillin include: • Amoxicillin • Ampicillin • Dicloxacillin • Indanylcarbencillin • Nafcillin • Oxacillin • Penicillin G • Penicillin V • Piperacillin • Ticarcillin
Classification of Penicillin
1. Narrow Spectrum Penicillin 1.Short acting penicillin ( Natural Penicillin) •Benzylpenicillin •Phenoxymethyl penicillin •Phenethecillin 2. Long Acting Penicillin •Procainepenicillin •Benethamine penicillin •Benzathinepenicillin 3.PenicillinaseResistant Penicillin •AntiStaphylococcalPenicillin •-Cloxacillin-Flucoxacillin– Methicillin –Dicloxacillin– Oxacillin–Nafcillin •Penicillin againstpenicillaseproducing gram –ivebacteria except pseudomonas •-Temocillin
2. Broad Spectrum Penicillin Ampicillin Amoxicillin Bacampicillin Pivampicillin Mezlocillin Talampiciilin Mezlocillin Ciclacillin
Broad Spectrum Penicillin Combinations • Combination of Amoxicillin with Calvulanic Acid • Combination of Ampicillin with Flucoxacillin • Combination of Ampicillin with Salbactam • Combination of Ticarcillin with Calvulanic acid
3. Anti pseudomonal Penicillin • Carbenicillin • Ticarcillin • Piperacillin Are antipesudomonal penicillin because of their activity against P.aeuroginosa. Piperacillin is the most potent of these antibiotics. They are effective against many gram –ive bacilli but not against klebsiella because of constitutive penicillinase.
Mechanism of Action of Penicillin • Penicillin are bactericidal. They inhibit the synthesis of bacterial cell wall. They interfere with last step of cell wall synthesis (transpeptidation or cross linkage) resulting in exposure of the osmotic ally less stable membrane. Cell lysis can occur either through osmotic pressure or through activation of autolysin. • These drugs are thus bactericidal, the success of penicillin antibiotic in causing cell death is related to Antibiotic size, charge and hydrophobicity. • Penicillin are effective only against rapidly growing micro organisms that synthesize peptidoglycan cell wall. Consequently they are inactive against organisms devoid of this structure such as mycobacteria, protozoa, fungi and viruses.
1. Penicillin Binding Protein • Penicillin inactivate numerous proteins on the bacteria cell membrane. These penicillin binding protein (PBPs) are bacterial enzymes involved in the synthesis of cell wall and in maintenance of morphological features of bacteria • Exposure of these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphological changes or lysis of susceptible bacteria. • The number of PBPs varies with type of organisms so alteration in some of target molecules can cause resistance For example Methicillin resistant staphylococcus aureus (MRSA) arose because of this resistant.
2. Inhibition of Transpeptidase • Some PBPs catalyze formation of cross linkage between peptidoglycan chain. Penicillin inhibit this transpeptidase catalyze reaction, thus hindering the formation of cross links essential for cell wall integrity.
3. Production of Autolysin • Many bacteria particularly Gram +ive cocci produce degradative enzyme (autolysin) that participate in normal remodeling of bacterial cell wall. • In the presence of penicillin, degradative action of autolysin proceeds in the absence of cell wall synthesis. Thus, antibacterial effect of penicillin is result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysin.
Resistance • Natural resistance to penicillin occur in organisms that either lack peptidoglycan cell wall for example mycoplasma or have cell walls that are impermeable to drug. Beta lactamase activity • This enzyme hydrolyze cyclic amide of ß lactam ring which result in loss of bactericidal activity. Decrease permeability to drug • Decrease penetration of antibiotic through cell membrane will prevent the drug to reach target PBPS. • Presence of efflux pump can also reduce amount of intracellular drug. Altered PBPs • Modified PBPs have lower affinity for ß lactam antibiotics requiring clinically unattainable concentration of drug to effect inhibition of bacterial growth
Pharmacokinetics • Route of administration of a ß-lactam antibiotic is determined by the stability of drug to a gastric acid and by severity of infection. • After oral administration absorption differs greatly for different penicillin.  Not absorbed: Carbenicillin, ticarcillin  Moderate absorbed: Benzyl penicillin ( penicillin G), ampicillin, Cloxacillin  Well absorbed: Phenoxymethyl penicillin ( Penicillin V), amoxicillin , bacampicillin, Talampicillin, Flucloxacillin, Ciclacillin. Absorption
Distribution • After absorption, penicillin's are widely distributed in body tissue and fluids. • Entry to CNS is poor. • This is compensated in treating meningitis by giving large IV oxacillin and Dicloxacillin.
Excretion • Most of the absorbed penicillin is rapidly excreted by kidneys into urine. • About 10% of the renal excretion is by glomerular filterationand 90% is by tubular secretion. • Ampicillin is excreted more slowly then penicillin G. • Naficillin is excreted 80% into bilary tract and only 20% by tubular secretion. • Penicillin is also excreted in sputum and milk. • Tubular secretion of penicillin can be partially blocked by probenecid. Dose modification is necessary in several renal failure.
Adverse Effects of Penicillin • Non toxic And Safe drugs • Allergic reactions may be severe. Major determinant of penicillin hypersentivity is penicilloic acid which reacts with protein and serve as hapten to cause immune reaction. Amoxicillin: rash 11 hours after administration
Other (Nonallergic) adverse effects include • Diarrhoea due to alteration in normal intestinal flora • Sometimes haemolytic, and thrombocytopenia or interstitial nephritis. • Penicillins are presented as their sodium or potassium salts. Physicians should be aware of this unexpected source of sodium or potassium, especially in patients with renal or cardiac disease. • Neurotoxic: Extremely high plasma penicillin concentrations cause convulsions. If injected intrathecally. • Decrease coaglation maybe observe with high doses of piperacillin, ticarcillin and nafcillin.
Cephalosporin
Meaning Cephalosporins are a large group of antibiotics derived from the mold Acremonium (previously called Cephalosporium).
Introduction • Cephalosporin are ß-lactam antibiotics that are closely related both structurally and functionally to penicillin. • Most Cephalosporin are produced semi- synthetically by the chemical attachment of side chain to 7-aminocephalosporinic acid. They were first obtained from fungus, cephalosporium.
Molecular Structure • They have nucleus of 7-aminocephalosporinic acid instead of penicillin, 6-aminopenicillinic acid. β-lactam ring
Cephalosporin Mode of Action • Cephalosporins are a type of β-lactam antibiotic closely related to the penicillins. They are bactericidal, with the same MOA as other beta-lactams. • Cephalosporins disrupt synthesis of the peptidoglycan layer of bacterial cell walls. Peptidoglycan is a strong structural molecule specific to the cells walls of bacteria. With the cell wall structure compromised, the bactericidal result is lysis and death of the cell. • Our cells do not have cells walls or peptidoglycan, therefore, B-lactam antibiotics are able to target bacterial cells without harming human cells.
Classification of Cephalosporin • They have been classified as 1st , 2nd , 3rd ,4th , and fifth generation based largely on their bacterial susceptibility pattern and resistant to ß lactamase.
First Generation The first generation of cephalosporin act as penicillin G substitutes. They are resistant to staphylcoccal penicillanase and also have activity againstt Proteus mirabilis, E.coli.  Cefazolin  Cefadroxil  Cephalexin  Cephalothin  Cephapirin  Cephradine • Cefazolin has longer duration of action and similar spectrum of action compared to other first generation drugs. • Cephalexin is the prototype of 1st generation oral cephalosporin . Oral administration twice daily is effective against pharyngitis.
Second Generation • Second generation display greater activity against 3 additional gram –ive organisms, H.influenza, Enterobacter aerogenes and some Neissseria Species whereas activity against gram +ive bacteria is weaker than 1st gen. • Antimicrobial coverage of cefotetan and cefoxitin also includes the anerobes, bacteroides fragilis..
 Cefuroxime sodium  Cefuroxime axetil  Cefmetazole  Cefotetan  Cefaclor  Cefamandole  Cefonicid  Cefoxitin • Cefuroxime sodium is a prototype 2nd generation parentral cephalosporin has a longer half life than similar agents. It cross the BBB and it can be used for community acquired bronchitis or penumonia or in eldery patient with immunocompromise. • Cefuroxime axetil administered twice daily, this drug is well absorbed and is active ß lactamase producing organism.
Third Generation • These have assumed an important role in treatment of infectious diseases. 3rd generation have enhanced activity against gram –ive bacilli as well as other enteric organisms plus serratia marcescens ( hosp. acquired infection from catheters)  Cefdinir  Cefixime  Cefotaxime  Ceftazidime  Ceftibuten  Ceftriaxone  cefoperazone
• Ceftriaxone and cefotaxime have become agent of choice in treatment of meningitis. • Cefidinir and Cefixime are administered orally once daily. • Cefotaxime penetrate well into CSF. • Ceftazidime is active against Pseudomonas aeruginosa. • Ceftriaxone has longest half life of any cephalosporin (6-8hr) which permits once a daily dosing. High level of this drug can be achieved in blood and CSF. it is effective against genital, anal and pharyngeal penicillin resistant Neisseria gonorrhea. • Ceftriaxone is excreted in bile and maybe use in patient with renal insufficiency. It has good penetration in bone.
Fourth Generation Cefepime is classified as 4th generation of cephalosporin and must be administered parenterally. Cefepime has a wide antibacterial spectrum, being active against streptococci and staphylococci ( but only those that are methicillin susceptible) Cefepime is also effective against gram –ive micro organism such as E.coli , K. penumoniae.
Fifth Generation • Ceftobiprole, • ceftaroline, • ceftolozane
Resistance • Mechanism of bacterial resistance to cephalosporin are essentially same as those described for penicillin.
Pharmacokinetic • Administration: All cephalosporin must be administered IV or IM because of their poor oral absorption except Cephlexin, cefadroxil, Cefadinir, Cefixime, Ceftibuten, Cefuroxime axetil
Distribution • All cephalosporin distribute very well into body fluids. However, adequate therapeutic level in CSF, regardless of inflammation are achieved. • Only with a select a few cephalosporin For example, ceftriaxone or cefotaxime is effective in treatment of neonatal and childhood meningitis caused by H.influenzae.
Elimination • Elimination occurs through tubular secretion or glomerular filtration. • Therefore doses must be adjusted in case of severe renal failure to guard against accumulation and toxicity. • An exception is ceftriaxone which is excreted through bile into feces and therefore is frequently employed in patients with renal insufficiency.
Adverse Drug Reactions • Incidence of adverse effects with cephalosporin Is relatively low. Allergy: allergic reactions of penicillin type is cross allergy between penicillin and cephalosporin's in about 10% patient. If a patient had a severe on immediate allergy reaction to penicillin then cephalosporin should not be used.
Other Common ADRs are: • Diarrhea • Nausea • Rash • Electrolyte Disturbances • Super infection
Other ß- Lactam Antibiotics
Carbapenems • Are synthetically ß-lactam antibiotics that differ in structure from penicillin in sulfur atom of thiazolidine ring has been externalized and replaced by carbon atom. Members: • Imipenem • Meropenem • Doripenem • Eratapenem
• They are broad spectrum antibiotic active against many aerobics and anaerobics. Gram +ive and gram –ive organisms. • They are highly resistant to ß- lactamase enzyme, making them very useful in treating bacterial infection. Where ß-lactamase is produce that make other ß-lactam antibiotics ineffective.
Monobactams • Monobactam which also disrupt cell wall synthesis. They are unique because ß- lactam is alone not fuse to any other. • Aztreonam , is only commercially available moobactam, has antimicrobial activity directed primarily against enterobacteriaceae, including P.aerugionsa. It lacks activity against gram +ive organism and anaerobes. • Aztreonam may offer a safe alternative for treating patients who are allergic and unable to tolerate penicillin or cephalosporin.
ß- Lactamase Inhibitors • Hydrolysis of ß lactam ring either by enzymatic cleavage with ß-lactamases or by acid, destroy the antimicrobial activity of ß-lactam antibiotic. ß- lactamase inhibitors include: • Clavulanic acid • Salbactam • Tezobactam
• ß lactamase inhibitors contain a ß- lactam ring but by themselves do not have significant antibacterial activity, Instead they bind to and inactivate ß- lactamase thereby protecting ß-lactam antibiotics that are normally substrate for this enzyme. • The ß-lactamase inhibitors are therefore formulated in combination with ß –lactamase sensitive antibiotics. • For example, Calvulanic acid + amoxicillin ( Co-Amoxiclav)
Other Cell Wall Inhibitors
Vancomycin • Vancomycin is an antibiotic ( tricyclic glycopeptide) that has become increasingly important because of its effectiveness against multiple drug resistant organisms, such as MRSA and enterococci. • it is active against wide variety of gram +ive bacteria. • It acts by inhibiting cell wall synthesis by peptidoglycan polymerization.
Adverse Effects • Fever • Chill • Phlebitis at infusion site • Ototoxicity and nephrotoxicity are more common when administered with another drug.
Daptomycin • It is a cyclic lipopeptide antibiotic, use in treatment of systemic and life threatening infections cause by gram+ive organisms.
Mechanism • Upon binding to bacterial cytoplasmic membrane, daptomycin induce rapid depolarization of membrane thus disrupting multiple aspects of membrane function and inhibiting intracellular synthesis of DNA, RNA and proteins. • Daptomycin is bactericidal and bacteria killing is concentration depending
Telavancin • Telavancin is a semi synthetic lipoglycopeptide antibiotic that is synthetic derivative of vancomycin. • It is alternative to vancomycin, daptomycin in treating complicated skin and skin structure infections caused by resistant gram +ive organism including MRSA. • Like vancomycin it also inhibit bacterial cell wall synthesis . • Unlike vancomycin, it exhibit an additional mechanism of action similar to daptomycin that involved distrutpion of bacterial cell membrane due to presence of liphophilic side chain moiety.
Protein Synthesis Inhibitors
Classes • Demeclocycline • Doxycycline • Minocycline • Tetracycline Tetracyclines • Tigecycline Glycycline • Amikacin • Gentamicin • Neomycin • Streptomycin • Tobramycin Aminoglycoside
• Azithromycin • Clarithromycin • Erythromycin • Telithromycin Macrolide • Chloramphenicol • Linezolid • Clindamycin • quinupristin Others
AminoGlycosides • Aminoglycosides are a group of bactericidal drug originally obtained from various streptomyces species. • Aminoglycoside antibiotics is associated with serious toxicities. They have been replaced to some extent by safer antibiotics, such as third and fourth generation of cephalosporins, the fluoroquinolones and the carbapenem.
Members • Amikacin • Gentamicin • Tobramycin • Kanamycin • Neomycin • Streptomycin
Mechanism of action • Aminoglycoside are bactericidal drugs • They cause the irreversible inhibition of bacterial protein synthesis. • After penetration through cell wall by active transport process as well as passive diffusion, the drug binds to receptors on 30S subunit of bacterial ribosome.
Inhibition of ribosomal protein synthesis is done by at least 3 ways 1. Interference with initiation complexes of peptide formation 2. Misreading of code on mRNA template which cause incorporation of incorrect amino acid into peptide 3. Breaking up of polysomes into non functional monosome.
Resistance 1. By decreased uptake of drug when oxygen dependent transport system for aminoglycoside is absent. 2. The micro organism produces a transferase enzyme or an enzyme that inactivate the aminoglycoside by adenylylation, acetylation or phosphorylation. This is principle type of resistance encountered clinically 3. The receptor protein on 30S ribosomal subunit maybe deleted or altered as a result of a mutation
Pharmacokinetics • Aminoglycoside are water soluble and do not readily cross cell membrane • They are not absorbed from gut and therefore must be given by injection for systemic infection • Penetration in CSF is poor. • Penetration in bile is moderate • Aminoglycoside cross placenta and may cause damage to 8th nerve un fetus. • There is no significant biotransformation. • Plasma half life is 2-4 hr • Excretion is mainly by glomerular filtration.
Therapeutic Use • Aminoglycoside are mainly used for: 1. Serious infection caused by gram –ive bacilli particularly septicemia, pelvic and abdominal sepsis. 2. They are almost always used in combination with ß-lactam antibiotic to extend coverage to include potential gram+ive pathogen.
Adverse Effects It is imp to monitor plasma levels of gentamicin, tobramycin and amikacin to avoid concentration that cause dose related toxicities. 1. Ototoxicity: directly related to higher peak plasma level and duration of treatment 2. Nephrotoxicity: retention of aminoglycoside by proximal tubular cells result in kidney damage.
Macrolides • Macrolide are a group of closely related compounds characterized by a macrocyclic lactone ring ( usually containing 14 or 16 atoms) to which deoxysugars are attached. • The prototype drug, erythromycin which consist of two sugar moieties attached to a 14 atom lactone ring, was obtained in 1952 from streptomyces erythreus. Clarithromycin and azithromycin are semi synthetic derivative of erythromycin.
Mechanism of action • It is primarily bacteriostatic drug. • It inhibits bacterial protein synthesis • It binds irreversibly to a site on 50S sub unit of bacterial ribosome, thus inhibiting translocation step of protein synthesis. • They also interfere at other step such as transpeptidation.
Resistance • Resistance to erythromycin is usually plasmid encoded. Three mechanisms have been identified. 1. Reduced permeability of cell membrane or active efflux 2. Production ( by enterobacteriaceae, large family of gram-ive) esterases that hydrolyze macrolide 3. Modification of ribosomal binding site by chromosomal mutation.
Antibacterial Spectrum Erythromycin: Is effective against many of same organism as penicillin G (streptococci etc) Telithromycin: has similar antibacterial spectrum similar to azithromycin Clarithrmycin: has spectrum of antibacterial activity similar to erythromycin but it is also effective against Haemophilus influenza, H.pylori Azithromycin: although less active against streptococci and staphylococci than erythromycin, azithromycin is far more active against respiratory infections (Bordetella pertussis and Legionella species. It also has activity against Mycoplasma pneumoniae, Treponema pallidum, Chlamydia species and Mycobacterium avium complex.)
Pharmacokinetic • Erythromycin base is destroyed by stomach acid and must be administered with enteric coating or esterified. • Food interferes with absorption • Clarithromycin, Azithromycin and Telithromycin are stable to stomach acid and are readily absorbed. • Erythromycin distributes well in body fluids except CSF. It is one of the few antibiotics that distributes in prostatic fluid and it has a unique characteristic of accumulating in marophages • All drugs concentrate in liver • Adjustment of renal failure is not necessary because they excreted in bile.
Adverse Effects 1. Epigastric Distress: This is common side effect and can lead to poor patient compliance to erythromycin 2. Cholestatic Jaundice ( retention of the constituents of bile in blood): Occurs with estolate forms of erythromycin. 3. Ototoxicity: Transient Deafness has been associated with erythromycin especially at high dosage 4. Other Allergic Reactions include fever, esinophilia and rashes
Contraindication • Patient with hepatic dysfunction should be treated caution.
Interactions • Erthromycin, Telithromycin and clarithromycin inhibit hepatic metabolism of a no. of drugs which can lead to toxic accumulation of these compounds. • No interactions have been reported for azithromycin
Clinical Uses Erythromycin is a drug of choice • in cornyebacterium infection ( diphtheria), • in respiratory infections, • neonatal, occular or genital chlamydial infections • and in treatment of community acquired penumonia.
Others
Chloramphenicol • It is active against a wide range of gram+ive and gram – ive organisms (bacteria, spirochetes, rickettsiae, chlamydiae and mycoplasmas.). However, because of its toxicity, its use is restricted to life threatning infections for which no alternative exist. • Chloramphenicol was first isolated in 1947 from culture of streptomyces venezulae
Mechanism of Action • The drug binds to bacterial ribosomal 50S subunit and inhibit protein synthesis at the peptidyltransferase reaction. Because of similarity of mammalian mitochondrial ribosomes to those of bacterial ribosomes, protein synthesis in these organelles maybe inhibited at high conc in blood producing bone marrow toxicity.
Adverse Drug Reaction 1. GI- Disturbances Nausea , vomiting, Diarrhea 2. Bone Marrow Disturbances: Anemia 3. Grey baby syndrome: this occurs in neonate if dosage regimen of chloramphenicol is not properly adjusted . Neonate have a low capacity to glucuronylated the antibiotic and they have underdeveloped renal function. Therefore neonate have decrease ability to excrete the drug, which accumulate to level that interfere with function of mitochondrial ribosome. this lead to poor feeding, depressed breathing, cardiovascular collapse, cyanosis ( hence name grey baby) and death. Adults can also exhibit this toxicity at high doses.
ANTI TB
TUBERCULOSIS • Chronic disease caused by Mycobacterium tuberculosis. • Tuberculosis typically attacks the lungs, but can also affect other parts of the body. • It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit respiratory fluids through the air.
Drugs used in TB FIRST LINE Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin SECOND LINE Ethionamide Thiacetazone Para Aminosalicylic acid (PAS) Amikacin Capreomycin Cycloserine Ciprofloxacin Kanamycin Rifabutin Rifapentine *RIPES
Isoniazid PHARMACOKINETICS Absorption • Rapid and complete; rate can be slowed with food • Peak Plasma Time: 1-2 hr Distribution • All body tissues and fluids including CSF; crosses placenta; enters breast milk • Protein Bound: 10-15% Metabolism • Hepatic Elimination • Excretion: Urine (75-95%); feces
Mechanism of Action • isoniazid targets the enzymes acyl carrier protein reductase (InhA) and β-ketoacyl-ACP synthase (KasA), which are essential for the synthesis of mycolic acid. Inhibiting mycolic acid leads to a disruption in the bacterial cell wall. Interactions: • INH can increase CBZ concentrations and cause CBZ toxicity. • Aluminum salts, decrease the absorption of INH. • INH may inhibit valproic acid hepatic metabolism. Contraindications: • Acute liver disease. • Lactation,seizure disorder.
ADRs • Hepatitis • Peripheral neuropathy • convulsions in patients prone to seizures • Hypersensitivity reactions with isoniazid include rashes and fever.
RIFAMPICIN Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active against gram positive and gram negative cocci, some enteric bacteria, mycobacteria and chlamydia. Mechanism • Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase and thereby inhibits RNA synthesis. • Resistance results from any one of several possible point mutations in repoB, the gene for the β subunit of RNA polymerase.
Pharmacokinetics Absorption • PO well absorbed; food may delay absorption • Peak plasma time: 2-4 hr Distribution • crosses blood-brain barrier well. • Protein bound: 80% Metabolism • Metabolized by liver. Elimination • Half-life: 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease, 1.8-11 hr • Excretion: Feces (60-65%) and urine (~30%) as unchanged drug
• Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea, vomiting, and rash. Hepatitis and death due to liver failure are rare. • Drug interactions: Because rifampin induces a number of cytochrome P450 enzymes, it can decrease the half-lives of co administered drugs that are metabolized by these enzymes. This may necessitate higher dosages for co administered drugs, a switch to drugs less affected by rifampin, or replacement of rifampin with rifabutin.
Pyrazinamide Pharmacokinetics • Absorption: well absorbed • Distribution: widely into body tissues and fluids including liver, lung, and CSF • Protein binding: 50% • Metabolism: hepatic • Half-life elimination: 9-10 hr • Time to peak, serum concentration: within 2 hr • Excretion: urine (4% as unchanged drug)
Mechanism of Action Pyrazinamide's exact mechanism of action is not known. Susceptible strains release pyrazinamidase, which converts PZA to pyrazinoic acid (POA). POA decreases the pH below that which retards the growth of M. tuberculosis and inhibiting the fatty acid synthesis .Studies indicate that PZA is most effective in the initial stages of treatment, which may be the result of diminished organism populations in macrophages early in therapy.
Adverse Effects • 1-10%: Malaise ( general feeling of discomfort, illness), Nausea, Vomiting , Anorexia, Arthralgia (pain in a joint), Myalgia (pain in a muscle) • <1%: Fever, Rash, Itching, Acne, Photosensitivity, Gout, Dysuria (the sensation of pain and/or burning, stinging, or itching of the urethra or urethral meatus associated with urination), Porphyria (a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system), Thrombocytopenia (deficiency of platelets in the blood), Hepatotoxicity, Interstitial nephritis ( the spaces between the kidney tubules become swollen (inflamed)). Interactions • PZA can increase serum uric acid levels and precipitate gout attacks, the dosages of antigout agents, including allopurinol, colchicine, probenecid , and sulfinpyrazone may need to be adjusted. • PZA is associated with dose-related hepatoxicity. Daily use of ethanol while receiving pyrazinamide increases the risk of drug-induced hepatitis.
Ethambutol Pharmacokinetics Absorption • Bioavailability: ~80% • Peak Plasma Time: 2-4 hr Distribution • Widely throughout body. • Protein binding: 20-30% Metabolism • Hepatic (20%) to inactive metabolite Elimination • Half-life elimination: 2.5-3.6 hr; 7-15 hr (end-stage renal disease) • Excretion: ~50% urine; ~50% feces as unchanged drug.
Mechanism Ethambutol inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. ADRS • Acute gout or hyperuricemia, Abdominal pain, Anaphylaxis, Confusion, disorientation, Fever, Headache, LFT abnormalities, Malaise, Nausea • Optic neuritis; symptoms may include decreased acuity (ability of the eye to distinguish shapes and the details of objects at a given distance), color blindness or visual defects (usually reversible with discontinuation). • Rash Drug Interactions • Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
Antiviral Drugs
Anti-viral drugs • Viruses have no cell wall and made up of nucleic acid components • Viruses containing envelope – antigenic in nature • Viruses are obligate intracellular parasite • They do not have a metabolic machinery of their own – uses host enzymes
Anti-viral drugs • Certain viruses multiply in the cytoplasm but others do in the nucleus • Most multiplication take place before diagnosis is made
Anti-Viral drugs • Many antiviral drugs are Purine or Pyrimidine analogs. • Many antiviral drugs are Prodrugs. They must be phosphorylated by viral or cellular enzymes in order to become active. • Anti-viral agents inhibits active replication so the viral growth resumes after drug removal.
Anti-viral drugs • Current anti-viral agents do not eliminate non-replicating or latent virus • Effective host immune response remains essential for the recovery from the viral infection • Clinical efficacy depends on achieving inhibitory conc. at the site of infection within the infected cells
Anti-viral drugs action Stages of viral replication • Cell entry – attachment - penetration • Uncoating • Transcription of viral genome • Translation • Assembly of virion components • Release
Amantadine mechanism of action:
Anti-viral drugs 1,Anti-herpes virus agents • Acyclovir / Valacyclovir • Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trifluridine / Idoxuridine / Vidarabine
Anti-viral drugs Acyclovir & Congeners : • Valacyclovir is a prodrug of Acyclovir with better bioavailability. • Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability. • Penciclovir is used only topically whereas Famciclovir can be administered orally.
Anti-Viral drugs PHARMACOLOGY OF ACYCLOVIR AND CONGENERS • Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs.
Anti-viral drugs Mechanism of action of Acyclovir and congeners : • All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. • The analog inhibits viral DNA-polymerase • Only actively replicating viruses are inhibited
Mechanism: ( Easy One) – Three phosphorylation steps for activation. • First converted to the monophosphate derivative by the virus-specified thymidine kinase;（selective activation） • Then to the di- and triphosphate compounds by host’s cellular enzymes. – Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: • Competitive inhibition of deoxyGTP for the viral DNA polymerase, with binding to the DNA template as an irreversible complex; • Incorporation into the viral DNA → chain termination
Anti-viral drugs • Acyclovir is thus selectively activated in cells infected with herpes virus. • Uninfected cells do not phosphorylate acyclovir.
Anti-Viral drugs Antiviral spectrum : • Acyclovir: HSV-1( is typically transmitted by oral-to-oral contact and causes infection in or around the mouth (oral herpes), but it can also cause genital herpes), HSV-2 ( is mainly sexually transmitted and causes genital herpes), VZV (chickenpox and herpes zoster (shingles)) • Ganciclovir / Cidofovir : CMV (mononucleosis or hepatitis (liver problem).) • Famciclovir : Herpes genitalis and shingles (painful rash) • Foscarnet : HSV, VZV, CMV, HIV • Penciclovir : Herpes labialis ( rash of the skin and mucous membranes,in particular, the lips)) • Trifluridine : Herpetic keratoconjunctivitis
Anti-Viral drugs Pharmacokinetics of Acyclovir : • Oral bioavailability ~ 20-30% • Distribution in all body tissues including CNS • Renal excretion: > 80% • Half lives: 2-5 hours • Administration: Topical, Oral , IV
Anti-viral drugs Adverse effects of Acyclovir / Ganciclovir • Nausea, vomiting and diarrhea • Nephrotoxicity - crystalluria, haematuria, renal insufficiency • Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir (a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets)
Anti-viral drugs Therapeutic uses : Acyclovir is the drug of choice for: • HSV Genital infections • HSV encephalitis • HSV infections in immunocompromised patient Ganciclovir is the drug of choice for: • CMV retinitis in immunocompromised patient • Prevention of CMV disease in transplant patients
Anti-viral drugs Cidofovir : • It is approved for the treatment of CMV retinitis in immunocompromised patients • It is a nucleotide analog of cytosine – no phosphorylation required. • It inhibits viral DNA synthesis • Available for IV, Intravitreal inj, topical • Nephrotoxicity is a major disadvantage.
Anti-viral drugs PHARMACOLOGY OF VIDARABINE • Vidarabine is a nucleoside analog. (adenosine) Antiviral spectrum of Vidarabine : HSV-1, HSV-2 and VZV. Its use is limited to HSV keratitis only
Anti-viral drugs Vidarabine • The drug is converted to its triphosphate analog which inhibits viral DNA-polymerase. • Oral bioavailability ~ 2% • Administration: Ophthalmic ointment • Used in HSV keratoconjunctivitis in immunocompromised patient. • Anemia and SIADH (Syndrome of inappropriate antidiuretic hormone secretion) are adverse effects.
Anti-viral drugs PHARMACOLOGY OF TRIFLURIDINE • Trifluridine is a Pyrimidine nucleoside analogs - inhibits viral DNA synthesis. Antiviral spectrum Trifluridine : • HSV-1, HSV-2 and VZV. • Use is limited to Topical - Ocular HSV Keratitis
Anti-viral drugs PHARMACOLOGY OF FOSCARNET • Foscarnet is an inorganic pyrophosphate analog • It directly inhibits viral DNA and RNA - polymerase and viral inverse transcriptase (it does not require phosphorylation for antiviral activity)
Anti-viral drugs Foscarnet • HSV-1, HSV-2, VZV, CMV and HIV. • Oral bioavailability ~ 10-20% • Distribution to all tissues including CNS • Administration: IV
Anti-viral drugs Adverse effects of Foscarnet • Hypocalcemia and hypomagnesemia (due to chelation of the drug with divalent cations) are common. • Neurotoxicity (headache, hallucinations, seizures) • Nephrotoxicity (acute tubular nephrosis is a condition that causes the lack of oxygen and blood flow to the kidneys, damaging them, interstitial nephritis)
Anti-viral drugs Therapeutic uses of Foscarnet • It is an alternative drug for • HSV infections (acyclovir resistant / immunocompromised patient ) • CMV retinitis (ganciclovir resistant / immunocompromised patient )
Anti-viral drugs Respiratory viral infections Influenza – • Amantadine / Rimantadine • Oseltamivir / Zanamavir (Neuraminidase inhibitors) RSV (Respiratory syncytial virus) bronchiolitis – • Ribavirin
Anti-viral drugs Amantadine and Rimantadine : Influenza (A,B,C,D) • Prevention & Treatment of influenza A • Inhibition of viral uncoating by inhibiting the viral membrane protein M2 OF Influenza A virus • Amantadine has anti- parkinsonian effects.
Anti-viral drugs Pharmacokinetics of Amantadine • Oral bioavailability ~ 50-90% • Amantadine cross extensively BBB whereas Rimantadine does not cross extensively . • Administration: Oral
Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • Influenza contains an enzyme neuraminidase which is essential for the replication of the virus. • Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell.
Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • These are effective against both types of influenza A and B. • Do not interfere with immune response to influenza A vaccine. • Can be used for both prophylaxis and acute treatment.
Anti-viral drugs
Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • Oseltamivir is orally administered. • Zanamavir is given intranasal. • Risk of bronchospasm with zanamavir
Anti-viral drugs PHARMACOLOGY OF RIBAVIRIN • Ribavirin is a guanosine analog. • Inhibition of RNA polymerase Antiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus
Anti-viral drugs Ribavirin : RSV (Respiratory syncytial virus) • Distribution in all body tissues, except CNS • Administration : Oral, IV, Inhalational in RSV. • Anemia and jaundice are adverse effects • Not advised in pregnancy.
Anti-viral drugs Therapeutic uses Ribavirin Ribavirin is the drug of choice for: • RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) • Lassa fever Ribavirin is an alternative drug for: • Influenza, parainfluenza, measles virus infection in immunocompromised patients
Anti-viral drugs Hepatic Viral infections : • Interferons • Lamivudine – cytosine analog – HBV • Entecavir – guanosine analog – HBV – lamivudine resistance strains • Ribavirin – Hepatitis C (with interferons)
Anti-viral drugs Interferons Interferons (IFNs) are natural proteins produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. • Antiviral, immune modulating (modify immune response) and anti-proliferative actions (inhibit growth) • Three classes of interferons – α , β, γ
Interferons • α and β interferons are produced by all the cells in response to viral infections • γ interferons are produced only by T lymphocyte (a lymphocyte of a type produced or processed by the thymus gland and actively participating in the immune response) and NK (a type of white blood cell) cells in response to cytokines – immune regulating effects • γ has less anti-viral activity compared to α and β interferons
Mechanism of action of Interferons : • Induction of the following enzymes: 1) a protein kinase which inhibits protein synthesis 2) an oligo-adenylate synthase which leads to degradation of viral mRNA 3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation
Anti-viral drugs Antiviral spectrum : Interferon α • Includes HBV, HCV and HPV (Human papillomavirus). • Anti-proliferative actions may inhibit the growth of certain cancers - like Kaposi sarcoma (disease in which cancer cells are found in the skin or mucous membranes that line the gastrointestinal (GI) tract, from mouth to anus, including the stomach and intestines.) and hairy cell leukemia (a type of cancer in which the bone marrow makes too many lymphocytes).
Anti-viral drugs Pharmacokinetics : Interferons • Oral bioavailability: < 1% • Administered Intralesionally, S.C, and I.V • Distribution in all body tissues, except CNS and eye. • Half lives: 1-4 hours
Anti-viral drugs Adverse effects of Interferons • Acute flu-like syndrome (fever, headache) • Bone marrow suppression (granulocytopenia, thrombocytopenia) • Neurotoxicity (confusion, seizures) • Cardiotoxicity - arrhythmia • Impairment of fertility
Anti-viral drugs Therapeutic uses Interferons • Chronic hepatitis B and C (complete disappearance is seen in 30%). • HZV infection (Herpes zoster, also known as shingles) in cancer patients (to prevent the dissemination of the infection) • CMV infections in renal transplant patients • Condylomata acuminata (given by intralesional injection). Complete clearance is seen ~ 50%. • Hairy cell leukemia (in combination with zidovudine) • AIDS related Kaposi’s sarcoma
Virus Diseases Drug(s) of choice Alternative drugs FLU A Influenza Amantadine Rimantadine RSV Pneumonia, bronchiolitis Ribavirin (aerosol) HSV Genital herpes Acyclovir Foscarnet Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine Encephalitis Acyclovir Neonatal HSV infection Acyclovir Vidarabine Herpes infections in immuno- compromised host Acyclovir Foscarnet
VZV In normal host No therapy In immunocompro- mised host, or during pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HIV AIDS HIV antibody positive with CD4 count < 500/mm3 Zidovudine ± protease inhibitors Didanosine, Stavudine HBV HCV Hepatitis B, C Interferons
ANTIFUNGALS
Introduction • Human fungal infection have increased dramatically in incidence and severity in recent years due to mainly advances in surgery, cancer treatment and critical care accompained by increase in use of broad spectrum antimicrobial and HIV. • Infectious diseases caused by fungi are called mycoses and they are often chronic in nature. • Some mycotic infections are superficial and some involve skin but fungi may penetrate into skin causing sub cutaneous infections. • The fungal infection that are most difficult to treat are systemic mycoses, which are often life threatening.
• Unlike bacteria, fungi are eukaryotic (Nucleus). They have rigid cell walls composed of largely of chitin rather than peptidoglycan. • The fungal cell membrane contain ergosterol rather than cholesterol found in mammalian membrane. These Chemical characteristic are in targeting chemotherapeutic agents against fungal infections. • Fungal infections are generally resistant to antibiotics used in treatment of bacterial infection and conversely bacteria are resistant to antifungal agents.
Classification of Antifungal Drugs 1. Drugs for Sub cutaneous and systemic mycoses : • Amphotericin B • Andidulafungin • Caspofungin • Fluconazole • Flucocytosine • Itraconazole • Ketoconazole • Micafungin • Posaconazole • voriconazole Mycoses that cause superficial infections of the epidermis, hair, and nails, are called cutaneous mycoses. Mycoses that penetrate the epidermis and the dermis to infect deeper tissues are called subcutaneous mycoses.
Classification of Antifungal Drugs 2. Drugs for cutaneous Mycoses: • Butenafine • Clotrimazole • Ciclopirox • Ecoconazole • Greisofulvin • Micoconazole • Naftifine • Nystatin • Oxiconazole • Sertaconazole • Sulconazole • Terbinafine • Terconazole • Tioconazole • tolnaftate
Drugs for subcutaneous and systemic mycotic infection
1. Amphotericin B • Amphotericin B is a naturally occurring polyene macrolide antibiotic produced by streptomyces nodosus. • Inspite of its toxicity, Amphotericin B is a drug of choice for treatment of systemic mycoses.
Mechanism of action • Several amphotericin B molecule bind to ergosterol in plasma membrane of sensitive fungal cell they form pores (channels) that require hydrophobic interactions between lipophilic segment of polyene antibiotic and the sterol. • The protein disrupts membrane function, allowing electrolytes ( particularly postassium) and small molecules to leak from cell, resulting in cell death.
PHARMACOLOGY OF AMPHOTERICIN B Chemistry -Amphotericin B is a polyene antibiotic (polyene: containing many double bonds) Mechanism of action -Binding to ergosterol present in the membranes of fungal cells  Formation of “pores” in the membrane  Leaking of small molecules (mainly K+) from the cells -The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
Antifungal Spectrum Amphotericin B is either fungicidal or fungistatic depending upon the on the organism and concentration of drug. It is effective against a wide range of fungi including: • Candida albican (is a naturally occurring fungus that lives on your body) • Histoplama capsulatum (is an environmental dimorphic fungus) • Cryptococcus neroforman (fungus that lives in the environment throughout the world.) • Aspergillus (Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide.)
Pharmacokinetic • Amphotericin B is administered by slow, Iv infusion. • The most dangerous intrathecal route is chosen for treatment of meningitis caused by fungi that are sensitive to drug • Amphotericin B has also been formulated with a variety of artificial lipids that form liposome • Amphotericin B is extensively bound to plasma proteins and is distributed throughout the body becoming highly bound tissue.
• Low level of drug and its metabolite appear in urine over a long period of time and some are also eliminated via bile. • To avoid nephrotoxicity, alternatives including sodium loading with infusion of normal saline and lipid base amphotericin B products are used.
Adverse Effects • Amphotericin B has low therapeutic index. 1. Fever and Chills: These occurs most commonly 1 to 3 hr after starting IV administration but they are usually subside with repeated administration 2. Renal Impairment: Despite the low level of drug excrete in urine patient may exhibit a decrease in glomerular filtration rate. Creatanine clearance can drop and K and Mg can are lost.
3. Hypotension: A shock life fall in blood pressure accompained by hypokalemia may occur, require potassium supplimentation 4. Anemia can occur due to suppression of erythropoietin production 5. Neurologic Effects can be seen with intrathecal administration of drug. 6. Thrombophlebitis (blocking due To clots)
Liposomal preparations of amphotericin B • Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing : • A. Nephrotoxicity • B. Infusion toxicity • Also, more effective • More expensive
2. Flucytosine (5-FC) • Flucytosine is a synthetic pyrimidine antimetabolite (inhibit metabolism) • that is often use in combination with amphotericin B.
Mechanism of action • 5 F-C (flucytosine) is taken by fungal cells via enzyme cytosine premase • It is converted intracellulary first to 5 FU and then to 5- fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP) which inhibits DNA & RNA synthesis respectively • Human cells are unable to convert parent drug into its active metabolite
3.Ketoconazole (AZOLE) • Ketoconazole was first orally active azole available for treatment of systemic mycoses.
Mechanism of action • Azoles are predominantly fungi static. • They inhibit C-14 α-demethylase ( a cytochrome P450 enzyme) thereby blocking the demethylation of lanosterol to ergosterol. The principle sterol of fungal membrane. • This inhibition disrupts membrane structure and function which in turn inhibits fungal cell growth. • Azoles are relatively Non-toxic • Most common adverse reaction is relatively minor gastrointestinal upset.
Drug Interaction & Contraindication • All azoles have been reported to cause abnormalities in liver enzyme. • By inhibiting cypP450, ketoconazole can potentiate the toxicities of other drugs such as cyclosporine and phenytoin and warfarin • Ketoconazole and amphotericin B should not be use together because the decrease in ergosterol in fungal membrane reduce the fungicidal action of amphotericin B.
Contraindication • Ketoconazole is teratogenicity in animals and is should not be given in pregnancy
Other Drugs Are: • Fluconazole • Itraconazole • Voriconazole • Posaconazole
Echinocandins • Echinocandins are antifungal drugs that inhibit the synthesis of glucan in cell wall via inhibition of all enzyme 1,3 ß glucan synthase. • 3 drugs from this class are currently used clinically: – Caspofungin – Micafungin – Anidulafungin
Caspofungin • It is the first member of echocandins class of antifungal drugs. • Caspofungin has activity against aspergillus and most candida species including those species that are resistant to azoles.
Adverse Effects include • Fever • Rash • Nausea • Phlebitis (inflammation of the walls of a vein) • Flushing occur due to release of histamine from mast cell
Drugs for cutaneous mycotic Infection • Mold like fungi that cause cutaneous skin infections are called dermatophytes or tinea. • These tinea are classified by the site of their infection such as tinea pedis, which refers to an infection of feets.
Squalene Epioxidase Inhibitor • These agents act by inhibiting squalene epioxide, resulting in blocking of biosynthesis of ergosterol, an essential component of fungal cell membrane. Drugs: 1. Terbinafine 2. Naftifine 3. Butenafine
Terbinafine • Oral terbinafine is a drug of choice for treating dermatophytoses especially onychomycoses (Nail infection) • Terbinafine hydrochloride, also known under the trade name Lamisil,is a synthetic allylamine antifungal developed by Novartis. It is highly hydrophobic in nature and tends to accumulate in skin, nails, and fatty tissues.
Mechanism of Action • Like Azole drugs, it interfere with ergosterol biosynthesis but rather than interacting with P450 system, terbinafine inhibits the fungal enzyme squalene epioxide. This leads to accumulation of sterol squalene which is toxic to organism. • Squalene epioxide is the enzyme that govern the conversion of squalene into ergosterol ( the major component of fungal cell membrane). If squalene epioxide is inhibited it will not converted to ergosterol and hence squalene starts accumulating in fungal cell, which leads to fungal cell death.
Antifungal Spectrum • The drug is primarily fungicidal. Topical terbinafie 1% cream and soultion are used to treat tinea pedis, tinea corporis ( Scalp), and tinea cruris ( groin area).
Griseofulvin • Griseofulvin has been largely replaced by oral terbinafine for the treatment of dermatophytic infections of the nails, although it is still used for ring worm and dermatophytosis of the skin and hair.
Mechanism of action • Griseofulvin mechanism of action at cellular level is unclear but it is deposited in newly forming skin where it binds to keratin, protecting skin from new infection. • Since its action is to prevent infection of these new skin structures, it must be administered for 2-6 weeks for skin and hair infection to allow replacement of infected keratin by resistant structure. • Nail infection may require therapy for months to allow regrowth of protected nail.
Other drugs are: • Nystatin ( binds to ergosterol in the fungal cell membrane, which leads to the formation of pores, ion leakage and ultimately fungal cell death) • Imidazole include ( Butoconazole, Clotrimazole, Oxiconazole, Ecoconazole etc),work as azole • Ciclopirox (Ciclopirox inhibit transport of essential elements thus result in Disruption of RNA , DNA and protein synthesis in fungal cell) • Tolnaftate (inhibit ergosterol synthesis)
ANTHELMINTIC DRUGS Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye.
Introduction to anthelmintics • Anthelmintics are drugs that are used to treat infections with parasitic worms. This includes both flat worms, e.g., flukes and tapeworms and round worms, i.e., nematodes.
225 INTRODUCTION • Humans are the primary hosts for the most of helminthic infections. • Most worms produce in human sexually by producing eggs and larvae (The larva is a worm-like creature, which emerges from an egg.) • These pass out of body and infect the secondary host • These invade humans via skin or GIT.
226 Types (clinical) 1. Worms live in hosts alimentary canal. E.g Tapeworm 2. Worms or larvae live in other tissues of host body like muscles , viscera , menninges , lungs, subcutaneous tissues. E.g: Taenia solium
ANTHELMINTIC DRUGS
Drugs for the treatment of Nematodes • Nematodes are elongated roundworms that posses a complete digestion system including both a mouth and an anus. • They cause infection of intestine as well as the blood and tissue.
229 MEBENDAZOLE(Vermox) • it is a synthetic benzimidazole • it has wider spectrum Mechanism of action: It inhibits microtubule synthesis in nematodes that irreversibly impairs glucose uptake. Intestinal parasites are immobilized and die slowy. It kills hook worm, pin worm , ascariasis and trichuris eggs.
230 Pharmacokinetics: • less than 10% of orally administered drug is absorbed • Absorption increases with fatty meal. • Absorbed drug is 90 % protein bound • It is converted to inactive metabolites rapidly in liver. • It has half life of 2-6 hours • It is primarily excreted in urine.
231 Thiabendazole • it is benzimidazole • it is chelating agent and form stable complexes with metals including iron, but does not bind with calcium. • it is rapidly absorbed • it has half life of 1.2 hrs • It is completely metabolized in liver and 90% is excreted in urine • it can also get absorbed through skin
232 Thiabendazole Mechanism of action: similar to other benzimidazoles (It inhibits microtubule synthesis ). It is ovicidal for some parasites. Adverse reactions and contraindications: • It is more toxic than other benzamidazoles • GI disturbances • Pruritus ,headache, drowsiness , psychoneurotic symptoms (anxiety, depression, or other feelings of unhappiness ). • Irreversible live failure. • Fatal Steven –Johnson syndrome(inflammation of skin) • Not used in children below 15 kg weight. pregnancy, hepatic and renal diseases.
233 PYRANTEL PAMOATE • It is a broad specturm anthelmintic. Pharmacokinetics: • It is poorly absorbed orally , • Half of the drug is excreted unchanged in the feces. Mechanism of action: • It is a depolrazing neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinestrase leads to paralizes of worms. The paralyzed worm is then expelled from the host intestinal tract.
234 Pyrental Pamoate Adverse Effects: • Infrequent mild transient GI disturbance • drowsiness , headache ,insomnia. • Rash ,fever Contraindications: • Should not be used in liver diseases. • Pregnancy • and child under 2 years of age
Drugs for the treatment of Trematodes • The trematodes (flukes) are leaf shaped flatworms that are generally characterized by the tissues they infect. • For example, they maybe categorized as liver, lung, intestinal or blood flukes.
Praziquantel • Agent of choice for treatment of all forms of schistosomiasis and other trematode infections. • Rapidly absorbed after oral administration and distributes into CSF. • High level occur in bile • Drug is excreted through urine and bile. • Contraindicated for occular cysticercosis because of destruction of the organism in the eye may damage the organ.
Mechanism of action • The mode of action is not exactly known at present, but experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. • The drug thereby induces contraction of the parasites, resulting in paralysis in the contracted state. • The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction (phagocytosis).
Drugs for the treatment of Cestodes • The cestodes or true tapeworms typically have a flat, segmented body and attach to the hosts intestine. • Like trematodes the tapeworms lack a mouth and a digestive tract throughout their life cycle.
239 NICLOSAMIDE • It is a useful drug for treatment of tape worm (cestodes) • Mechanism of action: • Adult worm is rapidly killed by inhibition of mitochondiral oxidative phosphorylation of adenosine diphosphate or stimulation of ATPase activity. Pharmacokinetics: • It is poorly absorbed from gut • Neither drug nor its metabolites are found in blood or urine
240 Niclosamide Adverse effects: • Mild ,infrequent and transitory GI disturbance • Alcohol consumption should be avoided • not indicated in children under 2 years of age.
241 ALBENDAZOLE • It is a broad spectrum • It is a drug of choice (primary therapeutic application) for treatment of hydatid disease or cystecercosis, it is also used for the treatment of intestinal nematodes like ascariasis ,tricurasis and strongyloidiasis , pinworm, hookworm
242 Albendazole Mechanism of action: It inhibits microtubule synthesis in nematodes(intestinal round worms) that irreversibly impairs glucose uptake, intestinal parasites are immobilized and die slowly. • It is larvicidal in hydatid ,cysticercosis , ascariasis and hook worm infection. • Also ovicidal in ascariasis , ancyclostomiasis(hookworm) , tricurasis
243 Pharmacokinetics (Albendazole) • It is benzimidazole • it is adminstered orally , and absorbed erratically (unpredictable) , absorption can be increased with fatty meal • It is metabolized in the liver rapidly to active metabolite albendazole sulphoxide
244 Pharmacokinetics (Albendazole) • It has a plasma half life of 8-12 hours • Sulphoxide is mostly protein bound , distributes well to tissues and enters bile, csf, hydated cyst • Metabolites are excreted in urine
245 Clinical uses (albendazole) • used on empty stomach when used against intraluminal parasites but with fatty meal when against tissue parasites. • In ascariasis ,tricurasis ,hookworm, pin worm infection : children under 2 years 400 mg orally as a single dose repeated for 2-3 days in heavy ascariasis ,repeated after 2-3 wks for pin worm 2. Hydated diseases: drug of choice ,400 mg twice with meals for 1 month or longer.
246 Albendazole 3. Neurocysticercosis: It is controversial as it has not proved superior to corticosteroid alone. It is used along with cotricosteroid to decrease the inflammation caused by dying organism and it also reduces the duration of course i.e. 400 mg twice daily for 21 days 4. Other infections: Drug of choice in cutaneous and visceral larvea migrans , intestinal cappillariasis and others
247 Albendazole Adverse effects: • In short term: use no significant adverse effects. • In long term use : as used in hydatid cyst and cysticercosis, abdominal distress, headache ,fever , fatigue, alopecia , increased liver enzymes , pancytopenia. Blood counts and LFT should be followed. • Not given during pregnancy and in hypersensitive people.
For Extra Information
249 INTESTINAL WORMS A) INTESTINAL ROUND WORMS (NEMATODES) • Ascaris lumbbricods (common round worm) • Enterobius vermicularis (pin worm) • Trichuris trichuria ( whip worm) • Strongyloids stercoralis ( thread worm) • Ankylostoma dudenale (hook worm)
250 Ascaris lumbricoids ( common round worm)
251 Hookworm
252 Pinworm male ,female
253 whipworm
254 Tricuris tricura(whip worm)
255 1. Alimentary canal(intestinal tape worms) B) TAPE WORMS (CESTODES) • Taenia saginata(Beaf) , • Taenia solium(Pork),Hymenolepis nana(Dwarf) ,diphylobothrium latum(Fish) • Humans become infected by eating raw or under cooked meat containing larvae of infected cattle or pig which has encysted in the animal muscle tissue.
256 Cestodes • In some conditions this larvae may develop in humans resulting cysticercosis (i.e. larvae gets encysted in the muscle and viscera or more seriously in the brain or eye.) • both adult worm and larvae can be present in the same host.
257 Tapeworm
258 cysticercosis
259 2. TISSUE WORMS A.TREMATODES(Schisotomes)OR FLUKES(leaf like) • Schistosoma haematobium • Schistosoma Japonicum • Schistosoma mansoni (These cause SCHISTASOMIASIS) also called (BILHARZIA) means disease of blood vessels. Adult worms of both sex live and mate in veins or venules of the gut wall or the bladder, eggs pass into the bladder or gut and produce inflammation of these organs , resulting in haematuria or loss of blood in feces.
• Paragonimus westermani (lung fluke) disease is caused by eating raw crab or fish , larvae move from intestine to blood and settle in lungs • Clonorchis sinensis(liver fluke) disease is caused by eating raw fish and worm settle in the biliary tract 260
261 Tissue worms • B. TISSUE ROUND WORMS Trichnella spiralis. Dracunulus medinensis (guinea worm)larva migrate from intestine to tissue of leg or foot and protrude out by making ulcer
FILARIAE includes Wuchereria bancrofti Loa loa Onchocerera volvulus Brugia malayi 262
263 Trichinela spiralis
264
ANTIPROTOZOAL
Introduction • Protozoal infections are common among people in underdeveloped tropical and subtropical countries, where sanitary conditions, hygienic practices and control of vectors for transmission are inadequate. • Most antiprotozoal agents have not proved to be safe for pregnant patients.
Protozoal infections 1. Amebiasis 2. Malaria 3. Giardiasis 4. Leshmaniasis 5. Toxoplasmosis 6. Trypanosomiasis
Protozoal infections 1. Difficult to be treated than bacterial infections. 2. Protozoal cells (Eukaryotes) have metabolic processes closer to human host than prokaryotic bacterial pathogens. 3. Many of antiprotozoal drugs cause toxic effects on the host. 4. Cells with high metabolic processes in the host are susceptible. 5. Examples: bone marrow stem, renal tubular cells, intestinal & neuronal cells. 6. Antiprotozoal are not safe during pregnancy.
Anti Protozoal Drugs 1. Amebiasis ( chloroquine, Dehydroemetine, emetine, iodoquinol, metronidazole, paromomysin, tinidazole) 2. Malaria (Artemisinin, chloroquine, mefloquine, primaquine, pyrimethamine, quinine/quinidine) 3. Trypanosomiasis (Benznidazole, Melarsoprol, Nifurtimox, pentamidine, suramin ) 4. Leishmaniasis (Sodium stibgluconate) 5. Toxoplasmosis (Pyrimethamine) 6. Giardiasis (Metronidazole, nitazoxanide, tinidazole)
AMOEBIASIS
Amebiasis Amebiasis is a protozoal infection of the intestinal tract that occurs due to ingestion of foods or water contaminated with Entameba Histolytica cysts
LIFE CYCLE Entamoeba histolytica exists in two forms: 1. Cysts (infective): • can survive outside the human body. • transform to trophozoites. 2. Trophozoites (non-infective; invasive): • Can reproduce • They may feed on intestinal bacteria or invade and ulcerate wall of large intestine, and may migrate to liver or other tissues. • transform to cysts which are excreted in feces.
Life Cycle 1. Cysts ingestion. 2. Formation of trophozoites 3. Penetration of intestinal wall 4. Multiplication of trophozoites within colon wall. 5. Systemic invasion. 6. Cyst formation in rectum and excretion in feces.
LIFE CYCLE
ANTIAMEBIC DRUGS ▪ Luminal Amebicides ▪ Tissue or systemic amebicides ▪ Mixed Amebicides
LUMEN AMOEBICIDES • Acts on the parasites in the lumen of the bowl. • used for treatment of asymptomatic amebiasis. Include • Diloxanide Furoate • Iodoquinol Antibiotics - Paromomycin - Tetracyclines - Erythromycin
 acts on the intestinal wall and liver (or any other extra-intestinal tissue).  Used for treatment of systemic form of the disease (intestinal wall infection or liver abscesses).  Emetine  Dehydroemetine  Chloroquine (liver only) Tissue Amoebicides (systemic)
Mixed amoebicides Effective against both luminal and systemic forms of the disease. Although luminal concentration is too low for single drug – treatment. • Metronidazol • Tinidazole
Drugs
METRONIDAZOLE • Mixed amoebicide. • Drug of choice for intestinal & extraintestinal amoebiasis. • Acts on trophozoites. • Has no effect on cysts. • Nitro group of metronidazole is reduced by protozoan leading to cytotoxic reduced product that binds to DNA and proteins resulting into parasite death.
Pharmacokinetics • Given orally or IV. • Absorption is rapid and complete. ▪ Due to rapid absorption from GIT, not reliably effective against luminal parasites. • Wide distribution to all tissues and body fluids (CSF, saliva, milk). • Plasma protein binding is low ( < 20%). • Plasma half life is 8 h
Pharmacokinetics • Metabolized in liver by mixed function oxidase followed by glucouroidation. • Excreted in urine as unchanged drug plus metabolites. • Clearance is decreased in liver impairment. Tinidazole has longer duration, simpler dosing regimen, less toxicity, than metronidazole, but is equally active.
Adverse effects 1. GIT: • Nausea • Vomiting • Dry mouth • Metallic taste • Diarrhoea • Oral Thrush (Moniliasis, yeast infection).
Adverse effects 2. CNS: Neurotoxicological effect – Insomnia, dizziness – peripheral neuropathy, paresthesia ( burning or prickling sensation) – Encphalopathy (disease of the brain that alters brain function or structure), convulsion ( IV infusion, rare). 3. Dysuria (Painful urination), dark urine. 4. Neutropenia 5. Disulfiram-like effect if taken with alcohol. nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort
Disulfiram like -effect When metronidazole is given with alcohol abdominal distress, nausea, vomiting, flushing, or headache, tachycardia, hyperventilation alcohol aldehyde dehydrogenase dehydrogenase Ethanol Acetaldehyde Acetate
EMETINE AND DEHYDROEMETINE Chemistry:  Emetine hydrochloride is a plant alkaloid (organic nitrogen-containing bases) derived from ipeca.  Dehydroemetine is a synthetic analogue Pharmacokinetics:  Erratic oral absorption.  Given preferably subcutaneously but could be given by IM.  Plasma half life is 5 days.
EMETINE • Concentrated in Liver, Lungs, Spleen, Kidney, Cardiac muscle and Intestinal wall. • Metabolized & Excreted slowly via kidney so it has a cumulative effect. • Trace amounts could be detected in urine 1-2 month after last dose. • Should not be used for more than 10 days (usually 3-5 days).
Mechanism • Act on tissue trophozoites causing irreversible block of protein synthesis.
Adverse Effects • Dehydroemetine is less toxic than emetine • pain at site of injection, abcesses ( painful collection of pus). GIT: nausea, vomiting, diarrhoea. Neuromuscular weakness Serious toxicities: cardiotoxicity - cardiac arrhythmias, - Hypotension - heart failure
Chloroquine • Antiamebic drug • Antimalarial drug • Used in combination with metronidazole and luminal amebicide for amebic liver diseases.
Luminal amoebicides • acts on the luminal parasites like Entamoeba histolytica (Amebae) Balantidium coli (Ciliates). • used for treatment of asymptomatic amebiasis. Include Diloxanide Furoate • Iodoquinol • Antibiotics - Paromomycin - Tetracyclines - Erythromycin
Diloxanide furoate Chemistry • Ester of diloxanide + furoic acid . Pharmacokinetics • Given orally. • Split in the intestine, most of diloxanide is absorbed, conjugated to form a glucoronide which is excreted in urine (90%). • The unabsorbed diloxanide is the amoebicidal agent (10%).
Pharmacodynamics: • Unkown mechanism of action • Direct amoebicidal action against luminal forms.
Therapeutic Uses • Drug of choice for asymptomatic intestinal infection. • For eradication of infection given along with all forms of amebiasis. • Dose: 500 mg three times/day for 10 days.
Adverse Effects • Flatulence • Nausea, vomiting, abdominal cramps. • No serious adverse effects Contraindications: - Pregnancy - Children (less than 2 years).
Paromomycin Sulphate • Aminoglycoside, not absorbed. • Effective against luminal forms of ameba Mechanism of action • Direct amebicidal action (causes leakage by its action on cell membrane of parasite). • Indirect killing of bacterial flora essential for proliferation of pathogenic amoebae.
Kinetics • Orally • Not significantly absorbed from the GIT • Small amount absorbed is excreted unchanged in urine (may accumulate with renal insufficiency).
Adverse effects • Gastrointestinal distress and diarrhea. Precautions • Severe renal disease • patients with GIT ulceration
Tetracyclines • Very weak direct amoebicidal action. • Mainly act indirectly on bacterial flora. • Used in severe cases of amoebic dysentery not responding to metronidazole combined with dehydroemetine.
HALOGENATED HYDROXYQUINOLINES • Iodoquinol Mechanism of action • Unknown • Effective against organisms in GIT only Not intestinal wall or liver. Pharmacokinetics • Absorption is poor, excreted in feces. • 10% enter circulation, excreted as glucouronide in urine. • Half life is 11-14 h
Uses • lumen amoebicide. • For eradication of infection given along with tissue amoebicide (metronidazole).
Adverse Effects • Peripheral neuropathy including optic neuritis • GIT: Nausea, vomiting, diarrhoea. • Enlargement of the thyroid gland. • Agranulocytosis (low number of granulocytes). • Iodine sensitivity. • interference with thyroid function tests (increase protein-bound serum iodine, decrease in measured 131I uptake).
Contraindications • Optic neuropathy • Thyroid disease • Sensitivity to iodine • Severe liver disease • Severe kidney disease • discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever)
Malaria
• Anti Malarials: The word "malaria" actually derives from the Italian for "bad air"-- the mal'aria associated with marshes and swamps. • Malaria is a febrile (related to fever) disease caused by a single-celled parasite known as a sporozoan (able to form spore-like cells, from which they get their name) and transmitted by a female mosquitoes of the genus Anopheles. • This sporozoan belongs to the genus Plasmodium, and the five species that infect humans are: • Plasmodium falciparum • Plasmodium malariae • Plasmodium ovale • Plasmodium vivax • Plasmodium knowlesi
• Signs and symptoms: • High grade fever • Headache • Spleenomegaly • Sweating and chills • Muscles aches • Nausea, vomitting and diarrhoea • Anemia etc
• Life cycle plasmodium: • Antimalarials: Agents used for treatment and prophylaxis of malaria.
PARASITE LIFE CYCLE An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.
• Classification: 1) 4-aminoquinolines: 5) Quinoline methanol • chloroquine . Mefloquine • hydroxy chloroquine 6) Biguanides • Amodiaquine . Proguanil 2) 8-aminoquinolines: . Chlorproguanil • Pamaquine 7) Sulfonamides and sulfones • Primaquine . Sulfadoxine, 3) Cinchona alkaloids: . Sulfamethopyrazine • Quinine 8) Sesquiterpene lactones • Quinidine . Artemether • Cinchonine . Artesunate • Cinchonidine 9) Naphthoquinone 4) Diaminopyrimidines: . Atorvaquone • Pyrimethamine 10) Combinations . sulfadoxine and pyrimethamine (chloroquine resistant P.falciparum) . sulfadoxine + pyrimethamine + Chloroquine
DRUG CLASSIFICATION Tissue schizonticides: eliminate developing or dormant liver forms; Blood schizonticides : act on erythrocytic parasites; Gametocides : kill sexual stages and prevent transmission to mosquitoes. Radical cure: eliminate both hepatic and erythrocytic stages. Not available.
Tissue schizonticides
PRIMAQUINE Hepatic stages of all human malaria parasites. Chemoprophylaxis against all malarial species. It is the only available agent active against the dormant stages of p vivax and p ovale. Gametocidal against the 4 human malaria species. Acts against erythrocytic stage parasites, but this activity is too weak to play an important role. MOA: is unknown.
MECHANISM OF ACTION Mechanism is not completely understood. Metabolites of primaquine are believed to act as oxidant that are responsible for schizonticidal actions as well as for the hemolysis.
ADVERSE EFFECTS Generally well tolerated. • GI disturbance, Headache •Leukopenia, Agranulocytosis, •Cardiac Arrhythmias, Hemolysis It is never given parenterally because it may induce marked hypotension. It should be avoided in pregnancy because the fetus is relatively G6PD(glucose-6-phosphate dehydrogenase)-deficient and thus at risk of hemolysis.
Blood Schizonticide
CHLOROQUINE  For treatment and chemoprophylaxis since the 1940s,(drug resistance). Oral use Antimalarial Action: Highly effective blood schizonticide.  Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum.  Not active against liver stage parasites.
MECHANISM OF ACTION Acts by : concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme.
CLINICAL USES Drug of choice in the treatment of nonfalciparum and sensitive falciparum malaria.  It is still used to treat falciparum : safety, low cost, antipyretic properties, and partial activity. Does not eliminate dormant liver forms of P vivax and P ovale, and for that reason Primaquine must be added for the radical cure of these species.
ADVERSE EFFECTS • Usually very well tolerated • Pruritus, GI disturbance, headache, malaise, blurring of vision, and urticaria • Rare : hemolysis in G6PD-deficient persons, impaired hearing, agranulocytosis, alopecia, bleaching of hair, hypotension, • Large IM injections or rapid IV infusions : severe hypotension and respiratory and cardiac arrest.
Mefloquine Used in chloroquine-resistant strains of P falciparum and other species. Is chemically related to quinine. Can only be given orally because severe local irritation occurs with parenteral use. Has strong blood schizonticidal activity against P falciparum and P vivax, it is not active against hepatic stages or gametocytes. MOA: The mechanism of action of mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects..
QUININE & QUINIDINE • First-line therapies for falciparum malaria. • Oral administration. • Higher plasma levels and half-life in infected persons than in healthy controls, but toxicity is not increased, apparently because of increased protein binding. • MOA: is unknown,
Antimalarial action  Is rapid-acting, highly effective blood schizonticide against the 4 species of human malaria parasites.  Gametocidal against p vivax and p ovale but not p falciparum  Not active against liver stage parasites.
ARTEMISININ & ITS DERIVATIVES Artemisinin: used orally. Analogs are:  Artesunate (water-soluble; oral, IM, IV and rectally), Artemether (lipid-soluble; oral, IM, and rectally), Dihydroartemisinin (water-soluble; oral). They are very rapidly acting blood schizonticides against all human malaria parasites, no effect on hepatic stages.
MOA The parasite when it infects a RBC, it consumes Hb within its digestive vacuole, liberating free heme, The iron in heme interacts with Artemisinin producing reactive oxygen radicals which damage the parasite leading to its death  Or inhibition of a parasite calcium transporter. Artemisinin-based combination therapy is now the standard for treatment of uncomplicated falciparum malaria in nearly all areas endemic for falciparum malaria. GI disturbance, dizziness, neutropenia, anemia, hemolysis, elevated liver enzymes, allergic reactions.
INHIBITORS OF FOLATE SYNTHESIS Pyrimethamine ,Proguanil ( Blood Schizonticide and Sporozoite) •Used in combination regimens, in the treatment and prevention of malaria. •Slowly but adequately absorbed from the GIT. Fansidar, a fixed combination of the sulfonamide sulfadoxine and pyrimethamine . Act slowly against erythrocytic forms of susceptible strains of all human malaria species. Proguanil also has some activity against hepatic forms. Neither drug is adequately gametocidal or effective against the persistent liver stages of p vivax or p ovale.
MECHANISM OF ACTION Selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. : GI Symptoms, Skin Rashes, Itching. Proguanil: Mouth Ulcers, Alopecia . Proguanil , Fansidar are considered safe in pregnancy
NURSING IMPLICATIONS
DRUG DOSES
UNIT 2; Anti Microbial.pptx
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UNIT 2; Anti Microbial.pptx

  • 1. Antimicrobial Drugs Dr. Shahid Khan, Pharm.D, RPh Lecturer, National Institute Of Health and Management Sciences (NiHMS), Peshawar
  • 3. Introduction Definition: Chemotherapy is the treatment of various diseases caused by pathogenic organisms (bacteria, fungi, viruses, protozoa, worms) with chemical substances, which due to their selective toxicity, destroy or remove pathogenic organisms without injuring the host. The chemical substances used for this purpose are chemotherapeutic agents. Drugs use for treatment of cancer ( Antineoplastic drugs) are also included in chemotherapy.
  • 4. History of Chemotherapy • The first drug used for cancer chemotherapy did not start out as a medicine. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. • Doctors reasoned that something that damaged the rapidly growing white blood cells might have a similar effect on cancer. So, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable.
  • 5.  Discovered first cure for syphilis  Neoarsphenamine was widely used for treatment of syphilis untill1945 when penicillin superseded it
  • 6.
  • 7. Antimicrobial Chemotherapy 1. Antibacterial Drugs: Antibiotics, Sulphonamide, Quinolone, Anti TB Drugs, Drugs for UTI etc 2. Antifungal Drugs 3. AntiViral Drugs 4. Anti Protozoal Drugs 5. Anthelmintics
  • 8. Why chemotherapy is different from other treatments • Treatments like radiation and surgery are considered local treatments. They act only in one area of the body such as the breast, lung, or prostate and usually target the cancer directly. • Chemotherapy differs from surgery or radiation in that it’s almost always used as a systemic treatment. • This means the drugs travel throughout the body to reach cancer cells wherever they are.
  • 9. Principle of Antimicrobial Therapy •Site of infection •Responsible organism •Sensitivity of drug Diagnosis •Acute infection require chemotherapy while chronic infection may not. •The chronic abscess respond poorly, although chemotherapy cover is essential if surgery is undertaken to avoid a flare-up of infection Decide Chemotherapy Is necessary •Specificity (spectrum of activity, antimicrobial activity of drug) •Pharmacokinetic factor •Patient related factor Select the drug
  • 10. Principle of Antimicrobial Therapy • Inadequate dose may develop resistance • Intermediate dose may not cure disease • Optimize dose should be use for therapy Frequency and Duration of Drug Administration • Acute infection treated for 5-10days • But for some infections such as TB, medication continue to avoid relapse Continue Therapy • After therapy, symptoms and signs may disappear before pathogen eradicated. Test for Cure
  • 11. Identification of infecting organisms • Characterizing the organism is central to selection of proper drug. • A rapid assessment can be made by gram staining which is useful in identifying presence of microorganisms in body fluids that are normally sterile ( Blood, Serum, CSF, Pleural Fluid, Peritoneal Fluid and urine). • However, it is necessary to culture infective microorganism to arrive at conclusive diagnosis. Thus it is imp to have sample prior to start treatment
  • 12. Empiric Therapy prior to identification of micro organism • Ideally, antimicrobial agent used to treat an infection is select after the organism has been identified and its drug susceptibility established. However in critical cases, wait can be dangerous. So immediate empiric therapy is indicated. • Broad spectrum therapy maybe indicated initially started when organism is unknown or polymicrobial infection is likely.
  • 13. Determining antimicrobial susceptibility of infective organism • After organism is cultured, its susceptibility to specific antibiotic serve as a guide in choosing antimicrobial therapy. • Some pathogens such as: Streptococcus pyogenes and Neisseria meningitis, usually have predictable susceptible pattern to certain antibiotics. • In contrast, most gram negative bacilli, enterococci and staphylococcus species often show unpredictable susceptibility to various antibiotics. Therefore require susceptibility testing to determine appropriate therapy.
  • 14. Bacteriostatic Vs Bacteriocidal • Antimicrobial drugs are classified as either bacteriostatic or bactericidal. • Bacteriostatic drugs arrest the growth and replication of bacteria at serum (or urine) levels achievable in patient thus limiting spread of infection. • Bactericidal drugs kill bacteria at drug serum levels achievable in the patient. Because of their severe action they are drug of choice in seriously ill patient. • Example: Chloramphenicol is bacteriostatic against gram –ive rods, and is bactericidal against other organisms such S.pneumoniae.
  • 15.
  • 16. MIC & MBC • MIC is minimum inhibitory concentration that is lowest concentration of antibiotic that inhibit bacterial growth. ( to provide effective therapy antibiotic conc. in body tissue and fluids should be greater than MIC) • MBC is minimum bactericidal concentration that kills the bacteria under investigation. The minimum bactericidal concentration (MBC) is lowest conc. of antimicrobial agent that kills 99.9%.
  • 17. Effect of site of infection on therapy • Adequate levels of antibiotic must reach site of infection for invading micro organism. • For this points of consideration are: 1. Lipid Solubility of drug 2. Molecular weight of drug 3. Protein binding of drug
  • 18. Patient Factors 1. Immune System: Elimination of infecting organism depends upon intact immune system. If weak then there will be problem 2. Renal Dysfunction: poor kidney function (10% or less of normal) causes accumulation of antibiotics that would otherwise easily eliminated. Dose adjustment needed!!! 3. Hepatic dysfunction: Antibiotics ( erythromycin and tetracycline) must use with caution. 4. Poor Perfusion: decrease circulation to anatomic areas such as lower limb, decrease the amount of antibiotic in that specific area. 5. Age: Renal/hepatic elimination processes are often poorly developed in newborns, making neonate vulnerable to toxic effects of chloramphenicol and sulfonamide. Young children should not treated with tetracycline or qunilone which affect bone growth.
  • 19. 6. Pregnancy: Many antibiotics cross placenta. Adverse effects are rare, except for tooth dysplasia and inhibition of bone growth encountered with tetracycline. 7. Lactation: Drug administered to a lactating mother may enter the nursing infant via breast milk. Although conc. Is low but the total dose to infant maybe sufficient to produce determental effects.
  • 20. Safety of Agent • Many antibiotics such as penicillin's, are among the least toxic of all drugs because they interfere with a site unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol) are less microorganism specific and are reserved for life threatening infections because of the drug’s potential for serious toxicity to patient.
  • 21. Route Of Administration • The oral route of administration is chosen for infections that are mild and is favorable for treatment on an outpatient basis. • In patients using IV in start should switch to oral agents should occur. • However, some antibiotics such as vancomycin, aminoglycosides and amphotericin B are so poorly absorbed from GIT that adequate serum levels cannot be obtained by oral administration.
  • 22. Determinants of Rational Dosing • Rational dosing depends upon drug pharmacodynamics (the relationship of dug conc. to antimicrobial effects) and pharmacokinetics (ADME) • Three imp properties that have a significant influence on the frequency of dosing are: 1. Conc. Dependent killing (e.g Aminoglycoside) 2. Time Dependent killing (e.g Beta lactam) 3. Postantibiotic effect (e.g fluroquinolones)
  • 23. Chemotherapeutic Spectra 1. Narrow Spectrum Antibiotics : chemotherapeutic agents acting only on a single or a limited group of micro organisms are said to have a narrow spectrum. For example, isoniazid is active only against mycobacteria. 2. Extended Spectrum Antibiotics: those antibiotics which are effective against gram positive organisms and also against a significant number of gram negative bacteria. For example, ampicillin 3. Broad Spectrum Antibiotics: drugs such as tetracycline and chloramphenicol affect a wide variety of microbes.
  • 24. Combination of Antimicrobial Drugs • It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility of super infection, decrease resistance, and minimize toxicity. • For example: In tuberculosis combination of therapy is used.
  • 25. Advantages & Disadvantages of combination • Advantages: certain combination of antibiotics such as beta lactam and aminoglycoside show synergism, means combination is more effective than alone. ( multiple drugs are only given in special situation when cause is unknown) • Disadvantages: A no. of antibiotics act only when micro organisms are multiplying. Thus, co administration of an agent that causes bacteriostasis plus second agent that is bactericidal may result in first interfering with the action of second. ( for example: bacteriostatic tetracycline drugs may interfere with bactericidal effect of penicillin and cephalosporin)
  • 26.
  • 27. Drug Resistance • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. • Some organisms are inherently resistant to an antibiotic. E.g Gram-ive organisms to vancomycin • Other causes are: 1. Genetic alteration  Mutation of DNA  DNA transfer of drug resistance 2. Altered expression of proteins in drug resistant micro organisms  Modification of target sites  Decrease accumulation  Enzymatic inactivation
  • 28. Prophylactic antibiotics • Antibiotics use for prevention rather than treatment. • Duration of prophylaxis should be closely observed to prevent unnecessary antibiotic exposure.
  • 29. Complication of Antibiotic therapy • Hypersensitivity ( Penicillin) • Direct toxicity (aminoglycoside cause ototoxicity) • Super infections (Broad spectrum antibiotics can suppress normal flora of the upper respiratory, intestinal, and genitourinary leading to overgrowth of opportunistic organisms especially fungi which is difficult to treat)
  • 31. The Action of Antimicrobial Drugs
  • 32. Cell wall Synthesis inhibitors • Some antimicrobial drugs selectively interfere with the synthesis of bacterial cell wall- a structure that mammalian cell do not posses. • The cell wall is composed of polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross links. • To be maximally effective, inhibitors of cell wall synthesis require actively proliferating micro organisms, they have little or no effect on bacteria that are not growing or dividing. • The most important member of the group are beta lactam antibiotics and vancomycin.
  • 34. Penicillin • First antibiotic, extracted from the mould, Pencillium notatum. The penicillins are among the most widely effective and least toxic drugs known, but increase resistance has limited their use. • Member of this family differ from one and another in R substituent attached to the 6-aminopencillianic acid residue. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, cross hypersensitivity and susceptibility to bacterial degradative enzymes (ß lactamases). • Benzylpenicillin ( penicillin G) was first natural penicillin available for clinical use. Other natural penicillin are phenoxymethylpenicillin (penicillin V) and phenethicillin. • All penicillin contain Penicillin nucleus ( 6-aminopenicillinic acid) consisting of a four membered beta lactam ring fused with a thiazolidine ring. The beta lactam rings carries a secondary amino group ( R-NH) where acidic radical can be attached to amino group at –R- thereby producing large number of semi synthetic penicillins with different properties.
  • 36. Members of Penicillin Penicillin include: • Amoxicillin • Ampicillin • Dicloxacillin • Indanylcarbencillin • Nafcillin • Oxacillin • Penicillin G • Penicillin V • Piperacillin • Ticarcillin
  • 38. 1. Narrow Spectrum Penicillin 1.Short acting penicillin ( Natural Penicillin) •Benzylpenicillin •Phenoxymethyl penicillin •Phenethecillin 2. Long Acting Penicillin •Procainepenicillin •Benethamine penicillin •Benzathinepenicillin 3.PenicillinaseResistant Penicillin •AntiStaphylococcalPenicillin •-Cloxacillin-Flucoxacillin– Methicillin –Dicloxacillin– Oxacillin–Nafcillin •Penicillin againstpenicillaseproducing gram –ivebacteria except pseudomonas •-Temocillin
  • 39. 2. Broad Spectrum Penicillin Ampicillin Amoxicillin Bacampicillin Pivampicillin Mezlocillin Talampiciilin Mezlocillin Ciclacillin
  • 40. Broad Spectrum Penicillin Combinations • Combination of Amoxicillin with Calvulanic Acid • Combination of Ampicillin with Flucoxacillin • Combination of Ampicillin with Salbactam • Combination of Ticarcillin with Calvulanic acid
  • 41. 3. Anti pseudomonal Penicillin • Carbenicillin • Ticarcillin • Piperacillin Are antipesudomonal penicillin because of their activity against P.aeuroginosa. Piperacillin is the most potent of these antibiotics. They are effective against many gram –ive bacilli but not against klebsiella because of constitutive penicillinase.
  • 42. Mechanism of Action of Penicillin • Penicillin are bactericidal. They inhibit the synthesis of bacterial cell wall. They interfere with last step of cell wall synthesis (transpeptidation or cross linkage) resulting in exposure of the osmotic ally less stable membrane. Cell lysis can occur either through osmotic pressure or through activation of autolysin. • These drugs are thus bactericidal, the success of penicillin antibiotic in causing cell death is related to Antibiotic size, charge and hydrophobicity. • Penicillin are effective only against rapidly growing micro organisms that synthesize peptidoglycan cell wall. Consequently they are inactive against organisms devoid of this structure such as mycobacteria, protozoa, fungi and viruses.
  • 43. 1. Penicillin Binding Protein • Penicillin inactivate numerous proteins on the bacteria cell membrane. These penicillin binding protein (PBPs) are bacterial enzymes involved in the synthesis of cell wall and in maintenance of morphological features of bacteria • Exposure of these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphological changes or lysis of susceptible bacteria. • The number of PBPs varies with type of organisms so alteration in some of target molecules can cause resistance For example Methicillin resistant staphylococcus aureus (MRSA) arose because of this resistant.
  • 44.
  • 45. 2. Inhibition of Transpeptidase • Some PBPs catalyze formation of cross linkage between peptidoglycan chain. Penicillin inhibit this transpeptidase catalyze reaction, thus hindering the formation of cross links essential for cell wall integrity.
  • 46. 3. Production of Autolysin • Many bacteria particularly Gram +ive cocci produce degradative enzyme (autolysin) that participate in normal remodeling of bacterial cell wall. • In the presence of penicillin, degradative action of autolysin proceeds in the absence of cell wall synthesis. Thus, antibacterial effect of penicillin is result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysin.
  • 47. Resistance • Natural resistance to penicillin occur in organisms that either lack peptidoglycan cell wall for example mycoplasma or have cell walls that are impermeable to drug. Beta lactamase activity • This enzyme hydrolyze cyclic amide of ß lactam ring which result in loss of bactericidal activity. Decrease permeability to drug • Decrease penetration of antibiotic through cell membrane will prevent the drug to reach target PBPS. • Presence of efflux pump can also reduce amount of intracellular drug. Altered PBPs • Modified PBPs have lower affinity for ß lactam antibiotics requiring clinically unattainable concentration of drug to effect inhibition of bacterial growth
  • 48. Pharmacokinetics • Route of administration of a ß-lactam antibiotic is determined by the stability of drug to a gastric acid and by severity of infection. • After oral administration absorption differs greatly for different penicillin.  Not absorbed: Carbenicillin, ticarcillin  Moderate absorbed: Benzyl penicillin ( penicillin G), ampicillin, Cloxacillin  Well absorbed: Phenoxymethyl penicillin ( Penicillin V), amoxicillin , bacampicillin, Talampicillin, Flucloxacillin, Ciclacillin. Absorption
  • 49. Distribution • After absorption, penicillin's are widely distributed in body tissue and fluids. • Entry to CNS is poor. • This is compensated in treating meningitis by giving large IV oxacillin and Dicloxacillin.
  • 50. Excretion • Most of the absorbed penicillin is rapidly excreted by kidneys into urine. • About 10% of the renal excretion is by glomerular filterationand 90% is by tubular secretion. • Ampicillin is excreted more slowly then penicillin G. • Naficillin is excreted 80% into bilary tract and only 20% by tubular secretion. • Penicillin is also excreted in sputum and milk. • Tubular secretion of penicillin can be partially blocked by probenecid. Dose modification is necessary in several renal failure.
  • 51. Adverse Effects of Penicillin • Non toxic And Safe drugs • Allergic reactions may be severe. Major determinant of penicillin hypersentivity is penicilloic acid which reacts with protein and serve as hapten to cause immune reaction. Amoxicillin: rash 11 hours after administration
  • 52. Other (Nonallergic) adverse effects include • Diarrhoea due to alteration in normal intestinal flora • Sometimes haemolytic, and thrombocytopenia or interstitial nephritis. • Penicillins are presented as their sodium or potassium salts. Physicians should be aware of this unexpected source of sodium or potassium, especially in patients with renal or cardiac disease. • Neurotoxic: Extremely high plasma penicillin concentrations cause convulsions. If injected intrathecally. • Decrease coaglation maybe observe with high doses of piperacillin, ticarcillin and nafcillin.
  • 54. Meaning Cephalosporins are a large group of antibiotics derived from the mold Acremonium (previously called Cephalosporium).
  • 55. Introduction • Cephalosporin are ß-lactam antibiotics that are closely related both structurally and functionally to penicillin. • Most Cephalosporin are produced semi- synthetically by the chemical attachment of side chain to 7-aminocephalosporinic acid. They were first obtained from fungus, cephalosporium.
  • 56. Molecular Structure • They have nucleus of 7-aminocephalosporinic acid instead of penicillin, 6-aminopenicillinic acid. β-lactam ring
  • 57. Cephalosporin Mode of Action • Cephalosporins are a type of β-lactam antibiotic closely related to the penicillins. They are bactericidal, with the same MOA as other beta-lactams. • Cephalosporins disrupt synthesis of the peptidoglycan layer of bacterial cell walls. Peptidoglycan is a strong structural molecule specific to the cells walls of bacteria. With the cell wall structure compromised, the bactericidal result is lysis and death of the cell. • Our cells do not have cells walls or peptidoglycan, therefore, B-lactam antibiotics are able to target bacterial cells without harming human cells.
  • 58.
  • 59. Classification of Cephalosporin • They have been classified as 1st , 2nd , 3rd ,4th , and fifth generation based largely on their bacterial susceptibility pattern and resistant to ß lactamase.
  • 60.
  • 61. First Generation The first generation of cephalosporin act as penicillin G substitutes. They are resistant to staphylcoccal penicillanase and also have activity againstt Proteus mirabilis, E.coli.  Cefazolin  Cefadroxil  Cephalexin  Cephalothin  Cephapirin  Cephradine • Cefazolin has longer duration of action and similar spectrum of action compared to other first generation drugs. • Cephalexin is the prototype of 1st generation oral cephalosporin . Oral administration twice daily is effective against pharyngitis.
  • 62. Second Generation • Second generation display greater activity against 3 additional gram –ive organisms, H.influenza, Enterobacter aerogenes and some Neissseria Species whereas activity against gram +ive bacteria is weaker than 1st gen. • Antimicrobial coverage of cefotetan and cefoxitin also includes the anerobes, bacteroides fragilis..
  • 63.  Cefuroxime sodium  Cefuroxime axetil  Cefmetazole  Cefotetan  Cefaclor  Cefamandole  Cefonicid  Cefoxitin • Cefuroxime sodium is a prototype 2nd generation parentral cephalosporin has a longer half life than similar agents. It cross the BBB and it can be used for community acquired bronchitis or penumonia or in eldery patient with immunocompromise. • Cefuroxime axetil administered twice daily, this drug is well absorbed and is active ß lactamase producing organism.
  • 64. Third Generation • These have assumed an important role in treatment of infectious diseases. 3rd generation have enhanced activity against gram –ive bacilli as well as other enteric organisms plus serratia marcescens ( hosp. acquired infection from catheters)  Cefdinir  Cefixime  Cefotaxime  Ceftazidime  Ceftibuten  Ceftriaxone  cefoperazone
  • 65. • Ceftriaxone and cefotaxime have become agent of choice in treatment of meningitis. • Cefidinir and Cefixime are administered orally once daily. • Cefotaxime penetrate well into CSF. • Ceftazidime is active against Pseudomonas aeruginosa. • Ceftriaxone has longest half life of any cephalosporin (6-8hr) which permits once a daily dosing. High level of this drug can be achieved in blood and CSF. it is effective against genital, anal and pharyngeal penicillin resistant Neisseria gonorrhea. • Ceftriaxone is excreted in bile and maybe use in patient with renal insufficiency. It has good penetration in bone.
  • 66. Fourth Generation Cefepime is classified as 4th generation of cephalosporin and must be administered parenterally. Cefepime has a wide antibacterial spectrum, being active against streptococci and staphylococci ( but only those that are methicillin susceptible) Cefepime is also effective against gram –ive micro organism such as E.coli , K. penumoniae.
  • 67. Fifth Generation • Ceftobiprole, • ceftaroline, • ceftolozane
  • 68.
  • 69. Resistance • Mechanism of bacterial resistance to cephalosporin are essentially same as those described for penicillin.
  • 70. Pharmacokinetic • Administration: All cephalosporin must be administered IV or IM because of their poor oral absorption except Cephlexin, cefadroxil, Cefadinir, Cefixime, Ceftibuten, Cefuroxime axetil
  • 71. Distribution • All cephalosporin distribute very well into body fluids. However, adequate therapeutic level in CSF, regardless of inflammation are achieved. • Only with a select a few cephalosporin For example, ceftriaxone or cefotaxime is effective in treatment of neonatal and childhood meningitis caused by H.influenzae.
  • 72. Elimination • Elimination occurs through tubular secretion or glomerular filtration. • Therefore doses must be adjusted in case of severe renal failure to guard against accumulation and toxicity. • An exception is ceftriaxone which is excreted through bile into feces and therefore is frequently employed in patients with renal insufficiency.
  • 73.
  • 74. Adverse Drug Reactions • Incidence of adverse effects with cephalosporin Is relatively low. Allergy: allergic reactions of penicillin type is cross allergy between penicillin and cephalosporin's in about 10% patient. If a patient had a severe on immediate allergy reaction to penicillin then cephalosporin should not be used.
  • 75. Other Common ADRs are: • Diarrhea • Nausea • Rash • Electrolyte Disturbances • Super infection
  • 76. Other ß- Lactam Antibiotics
  • 77.
  • 78. Carbapenems • Are synthetically ß-lactam antibiotics that differ in structure from penicillin in sulfur atom of thiazolidine ring has been externalized and replaced by carbon atom. Members: • Imipenem • Meropenem • Doripenem • Eratapenem
  • 79. • They are broad spectrum antibiotic active against many aerobics and anaerobics. Gram +ive and gram –ive organisms. • They are highly resistant to ß- lactamase enzyme, making them very useful in treating bacterial infection. Where ß-lactamase is produce that make other ß-lactam antibiotics ineffective.
  • 80. Monobactams • Monobactam which also disrupt cell wall synthesis. They are unique because ß- lactam is alone not fuse to any other. • Aztreonam , is only commercially available moobactam, has antimicrobial activity directed primarily against enterobacteriaceae, including P.aerugionsa. It lacks activity against gram +ive organism and anaerobes. • Aztreonam may offer a safe alternative for treating patients who are allergic and unable to tolerate penicillin or cephalosporin.
  • 81. ß- Lactamase Inhibitors • Hydrolysis of ß lactam ring either by enzymatic cleavage with ß-lactamases or by acid, destroy the antimicrobial activity of ß-lactam antibiotic. ß- lactamase inhibitors include: • Clavulanic acid • Salbactam • Tezobactam
  • 82. • ß lactamase inhibitors contain a ß- lactam ring but by themselves do not have significant antibacterial activity, Instead they bind to and inactivate ß- lactamase thereby protecting ß-lactam antibiotics that are normally substrate for this enzyme. • The ß-lactamase inhibitors are therefore formulated in combination with ß –lactamase sensitive antibiotics. • For example, Calvulanic acid + amoxicillin ( Co-Amoxiclav)
  • 83. Other Cell Wall Inhibitors
  • 84. Vancomycin • Vancomycin is an antibiotic ( tricyclic glycopeptide) that has become increasingly important because of its effectiveness against multiple drug resistant organisms, such as MRSA and enterococci. • it is active against wide variety of gram +ive bacteria. • It acts by inhibiting cell wall synthesis by peptidoglycan polymerization.
  • 85. Adverse Effects • Fever • Chill • Phlebitis at infusion site • Ototoxicity and nephrotoxicity are more common when administered with another drug.
  • 86. Daptomycin • It is a cyclic lipopeptide antibiotic, use in treatment of systemic and life threatening infections cause by gram+ive organisms.
  • 87. Mechanism • Upon binding to bacterial cytoplasmic membrane, daptomycin induce rapid depolarization of membrane thus disrupting multiple aspects of membrane function and inhibiting intracellular synthesis of DNA, RNA and proteins. • Daptomycin is bactericidal and bacteria killing is concentration depending
  • 88. Telavancin • Telavancin is a semi synthetic lipoglycopeptide antibiotic that is synthetic derivative of vancomycin. • It is alternative to vancomycin, daptomycin in treating complicated skin and skin structure infections caused by resistant gram +ive organism including MRSA. • Like vancomycin it also inhibit bacterial cell wall synthesis . • Unlike vancomycin, it exhibit an additional mechanism of action similar to daptomycin that involved distrutpion of bacterial cell membrane due to presence of liphophilic side chain moiety.
  • 90. Classes • Demeclocycline • Doxycycline • Minocycline • Tetracycline Tetracyclines • Tigecycline Glycycline • Amikacin • Gentamicin • Neomycin • Streptomycin • Tobramycin Aminoglycoside
  • 91. • Azithromycin • Clarithromycin • Erythromycin • Telithromycin Macrolide • Chloramphenicol • Linezolid • Clindamycin • quinupristin Others
  • 92. AminoGlycosides • Aminoglycosides are a group of bactericidal drug originally obtained from various streptomyces species. • Aminoglycoside antibiotics is associated with serious toxicities. They have been replaced to some extent by safer antibiotics, such as third and fourth generation of cephalosporins, the fluoroquinolones and the carbapenem.
  • 93. Members • Amikacin • Gentamicin • Tobramycin • Kanamycin • Neomycin • Streptomycin
  • 94. Mechanism of action • Aminoglycoside are bactericidal drugs • They cause the irreversible inhibition of bacterial protein synthesis. • After penetration through cell wall by active transport process as well as passive diffusion, the drug binds to receptors on 30S subunit of bacterial ribosome.
  • 95. Inhibition of ribosomal protein synthesis is done by at least 3 ways 1. Interference with initiation complexes of peptide formation 2. Misreading of code on mRNA template which cause incorporation of incorrect amino acid into peptide 3. Breaking up of polysomes into non functional monosome.
  • 96. Resistance 1. By decreased uptake of drug when oxygen dependent transport system for aminoglycoside is absent. 2. The micro organism produces a transferase enzyme or an enzyme that inactivate the aminoglycoside by adenylylation, acetylation or phosphorylation. This is principle type of resistance encountered clinically 3. The receptor protein on 30S ribosomal subunit maybe deleted or altered as a result of a mutation
  • 97. Pharmacokinetics • Aminoglycoside are water soluble and do not readily cross cell membrane • They are not absorbed from gut and therefore must be given by injection for systemic infection • Penetration in CSF is poor. • Penetration in bile is moderate • Aminoglycoside cross placenta and may cause damage to 8th nerve un fetus. • There is no significant biotransformation. • Plasma half life is 2-4 hr • Excretion is mainly by glomerular filtration.
  • 98. Therapeutic Use • Aminoglycoside are mainly used for: 1. Serious infection caused by gram –ive bacilli particularly septicemia, pelvic and abdominal sepsis. 2. They are almost always used in combination with ß-lactam antibiotic to extend coverage to include potential gram+ive pathogen.
  • 99. Adverse Effects It is imp to monitor plasma levels of gentamicin, tobramycin and amikacin to avoid concentration that cause dose related toxicities. 1. Ototoxicity: directly related to higher peak plasma level and duration of treatment 2. Nephrotoxicity: retention of aminoglycoside by proximal tubular cells result in kidney damage.
  • 100. Macrolides • Macrolide are a group of closely related compounds characterized by a macrocyclic lactone ring ( usually containing 14 or 16 atoms) to which deoxysugars are attached. • The prototype drug, erythromycin which consist of two sugar moieties attached to a 14 atom lactone ring, was obtained in 1952 from streptomyces erythreus. Clarithromycin and azithromycin are semi synthetic derivative of erythromycin.
  • 101.
  • 102. Mechanism of action • It is primarily bacteriostatic drug. • It inhibits bacterial protein synthesis • It binds irreversibly to a site on 50S sub unit of bacterial ribosome, thus inhibiting translocation step of protein synthesis. • They also interfere at other step such as transpeptidation.
  • 103.
  • 104.
  • 105. Resistance • Resistance to erythromycin is usually plasmid encoded. Three mechanisms have been identified. 1. Reduced permeability of cell membrane or active efflux 2. Production ( by enterobacteriaceae, large family of gram-ive) esterases that hydrolyze macrolide 3. Modification of ribosomal binding site by chromosomal mutation.
  • 106. Antibacterial Spectrum Erythromycin: Is effective against many of same organism as penicillin G (streptococci etc) Telithromycin: has similar antibacterial spectrum similar to azithromycin Clarithrmycin: has spectrum of antibacterial activity similar to erythromycin but it is also effective against Haemophilus influenza, H.pylori Azithromycin: although less active against streptococci and staphylococci than erythromycin, azithromycin is far more active against respiratory infections (Bordetella pertussis and Legionella species. It also has activity against Mycoplasma pneumoniae, Treponema pallidum, Chlamydia species and Mycobacterium avium complex.)
  • 107. Pharmacokinetic • Erythromycin base is destroyed by stomach acid and must be administered with enteric coating or esterified. • Food interferes with absorption • Clarithromycin, Azithromycin and Telithromycin are stable to stomach acid and are readily absorbed. • Erythromycin distributes well in body fluids except CSF. It is one of the few antibiotics that distributes in prostatic fluid and it has a unique characteristic of accumulating in marophages • All drugs concentrate in liver • Adjustment of renal failure is not necessary because they excreted in bile.
  • 108. Adverse Effects 1. Epigastric Distress: This is common side effect and can lead to poor patient compliance to erythromycin 2. Cholestatic Jaundice ( retention of the constituents of bile in blood): Occurs with estolate forms of erythromycin. 3. Ototoxicity: Transient Deafness has been associated with erythromycin especially at high dosage 4. Other Allergic Reactions include fever, esinophilia and rashes
  • 109. Contraindication • Patient with hepatic dysfunction should be treated caution.
  • 110. Interactions • Erthromycin, Telithromycin and clarithromycin inhibit hepatic metabolism of a no. of drugs which can lead to toxic accumulation of these compounds. • No interactions have been reported for azithromycin
  • 111. Clinical Uses Erythromycin is a drug of choice • in cornyebacterium infection ( diphtheria), • in respiratory infections, • neonatal, occular or genital chlamydial infections • and in treatment of community acquired penumonia.
  • 112. Others
  • 113. Chloramphenicol • It is active against a wide range of gram+ive and gram – ive organisms (bacteria, spirochetes, rickettsiae, chlamydiae and mycoplasmas.). However, because of its toxicity, its use is restricted to life threatning infections for which no alternative exist. • Chloramphenicol was first isolated in 1947 from culture of streptomyces venezulae
  • 114. Mechanism of Action • The drug binds to bacterial ribosomal 50S subunit and inhibit protein synthesis at the peptidyltransferase reaction. Because of similarity of mammalian mitochondrial ribosomes to those of bacterial ribosomes, protein synthesis in these organelles maybe inhibited at high conc in blood producing bone marrow toxicity.
  • 115. Adverse Drug Reaction 1. GI- Disturbances Nausea , vomiting, Diarrhea 2. Bone Marrow Disturbances: Anemia 3. Grey baby syndrome: this occurs in neonate if dosage regimen of chloramphenicol is not properly adjusted . Neonate have a low capacity to glucuronylated the antibiotic and they have underdeveloped renal function. Therefore neonate have decrease ability to excrete the drug, which accumulate to level that interfere with function of mitochondrial ribosome. this lead to poor feeding, depressed breathing, cardiovascular collapse, cyanosis ( hence name grey baby) and death. Adults can also exhibit this toxicity at high doses.
  • 117. TUBERCULOSIS • Chronic disease caused by Mycobacterium tuberculosis. • Tuberculosis typically attacks the lungs, but can also affect other parts of the body. • It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit respiratory fluids through the air.
  • 118. Drugs used in TB FIRST LINE Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin SECOND LINE Ethionamide Thiacetazone Para Aminosalicylic acid (PAS) Amikacin Capreomycin Cycloserine Ciprofloxacin Kanamycin Rifabutin Rifapentine *RIPES
  • 119. Isoniazid PHARMACOKINETICS Absorption • Rapid and complete; rate can be slowed with food • Peak Plasma Time: 1-2 hr Distribution • All body tissues and fluids including CSF; crosses placenta; enters breast milk • Protein Bound: 10-15% Metabolism • Hepatic Elimination • Excretion: Urine (75-95%); feces
  • 120. Mechanism of Action • isoniazid targets the enzymes acyl carrier protein reductase (InhA) and β-ketoacyl-ACP synthase (KasA), which are essential for the synthesis of mycolic acid. Inhibiting mycolic acid leads to a disruption in the bacterial cell wall. Interactions: • INH can increase CBZ concentrations and cause CBZ toxicity. • Aluminum salts, decrease the absorption of INH. • INH may inhibit valproic acid hepatic metabolism. Contraindications: • Acute liver disease. • Lactation,seizure disorder.
  • 121. ADRs • Hepatitis • Peripheral neuropathy • convulsions in patients prone to seizures • Hypersensitivity reactions with isoniazid include rashes and fever.
  • 122. RIFAMPICIN Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active against gram positive and gram negative cocci, some enteric bacteria, mycobacteria and chlamydia. Mechanism • Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase and thereby inhibits RNA synthesis. • Resistance results from any one of several possible point mutations in repoB, the gene for the β subunit of RNA polymerase.
  • 123.
  • 124. Pharmacokinetics Absorption • PO well absorbed; food may delay absorption • Peak plasma time: 2-4 hr Distribution • crosses blood-brain barrier well. • Protein bound: 80% Metabolism • Metabolized by liver. Elimination • Half-life: 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease, 1.8-11 hr • Excretion: Feces (60-65%) and urine (~30%) as unchanged drug
  • 125. • Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea, vomiting, and rash. Hepatitis and death due to liver failure are rare. • Drug interactions: Because rifampin induces a number of cytochrome P450 enzymes, it can decrease the half-lives of co administered drugs that are metabolized by these enzymes. This may necessitate higher dosages for co administered drugs, a switch to drugs less affected by rifampin, or replacement of rifampin with rifabutin.
  • 126. Pyrazinamide Pharmacokinetics • Absorption: well absorbed • Distribution: widely into body tissues and fluids including liver, lung, and CSF • Protein binding: 50% • Metabolism: hepatic • Half-life elimination: 9-10 hr • Time to peak, serum concentration: within 2 hr • Excretion: urine (4% as unchanged drug)
  • 127. Mechanism of Action Pyrazinamide's exact mechanism of action is not known. Susceptible strains release pyrazinamidase, which converts PZA to pyrazinoic acid (POA). POA decreases the pH below that which retards the growth of M. tuberculosis and inhibiting the fatty acid synthesis .Studies indicate that PZA is most effective in the initial stages of treatment, which may be the result of diminished organism populations in macrophages early in therapy.
  • 128. Adverse Effects • 1-10%: Malaise ( general feeling of discomfort, illness), Nausea, Vomiting , Anorexia, Arthralgia (pain in a joint), Myalgia (pain in a muscle) • <1%: Fever, Rash, Itching, Acne, Photosensitivity, Gout, Dysuria (the sensation of pain and/or burning, stinging, or itching of the urethra or urethral meatus associated with urination), Porphyria (a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system), Thrombocytopenia (deficiency of platelets in the blood), Hepatotoxicity, Interstitial nephritis ( the spaces between the kidney tubules become swollen (inflamed)). Interactions • PZA can increase serum uric acid levels and precipitate gout attacks, the dosages of antigout agents, including allopurinol, colchicine, probenecid , and sulfinpyrazone may need to be adjusted. • PZA is associated with dose-related hepatoxicity. Daily use of ethanol while receiving pyrazinamide increases the risk of drug-induced hepatitis.
  • 129. Ethambutol Pharmacokinetics Absorption • Bioavailability: ~80% • Peak Plasma Time: 2-4 hr Distribution • Widely throughout body. • Protein binding: 20-30% Metabolism • Hepatic (20%) to inactive metabolite Elimination • Half-life elimination: 2.5-3.6 hr; 7-15 hr (end-stage renal disease) • Excretion: ~50% urine; ~50% feces as unchanged drug.
  • 130. Mechanism Ethambutol inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. ADRS • Acute gout or hyperuricemia, Abdominal pain, Anaphylaxis, Confusion, disorientation, Fever, Headache, LFT abnormalities, Malaise, Nausea • Optic neuritis; symptoms may include decreased acuity (ability of the eye to distinguish shapes and the details of objects at a given distance), color blindness or visual defects (usually reversible with discontinuation). • Rash Drug Interactions • Aluminum hydroxide can reduce the rate or extent of ethambutol absorption. At least 4 hours should elapse between doses of aluminum hydroxide-containing antacids and ethambutol.
  • 132. Anti-viral drugs • Viruses have no cell wall and made up of nucleic acid components • Viruses containing envelope – antigenic in nature • Viruses are obligate intracellular parasite • They do not have a metabolic machinery of their own – uses host enzymes
  • 133. Anti-viral drugs • Certain viruses multiply in the cytoplasm but others do in the nucleus • Most multiplication take place before diagnosis is made
  • 134. Anti-Viral drugs • Many antiviral drugs are Purine or Pyrimidine analogs. • Many antiviral drugs are Prodrugs. They must be phosphorylated by viral or cellular enzymes in order to become active. • Anti-viral agents inhibits active replication so the viral growth resumes after drug removal.
  • 135. Anti-viral drugs • Current anti-viral agents do not eliminate non-replicating or latent virus • Effective host immune response remains essential for the recovery from the viral infection • Clinical efficacy depends on achieving inhibitory conc. at the site of infection within the infected cells
  • 136. Anti-viral drugs action Stages of viral replication • Cell entry – attachment - penetration • Uncoating • Transcription of viral genome • Translation • Assembly of virion components • Release
  • 137.
  • 139.
  • 140. Anti-viral drugs 1,Anti-herpes virus agents • Acyclovir / Valacyclovir • Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trifluridine / Idoxuridine / Vidarabine
  • 141. Anti-viral drugs Acyclovir & Congeners : • Valacyclovir is a prodrug of Acyclovir with better bioavailability. • Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability. • Penciclovir is used only topically whereas Famciclovir can be administered orally.
  • 142. Anti-Viral drugs PHARMACOLOGY OF ACYCLOVIR AND CONGENERS • Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs.
  • 143. Anti-viral drugs Mechanism of action of Acyclovir and congeners : • All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. • The analog inhibits viral DNA-polymerase • Only actively replicating viruses are inhibited
  • 144. Mechanism: ( Easy One) – Three phosphorylation steps for activation. • First converted to the monophosphate derivative by the virus-specified thymidine kinase;（selective activation） • Then to the di- and triphosphate compounds by host’s cellular enzymes. – Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: • Competitive inhibition of deoxyGTP for the viral DNA polymerase, with binding to the DNA template as an irreversible complex; • Incorporation into the viral DNA → chain termination
  • 145.
  • 146. Anti-viral drugs • Acyclovir is thus selectively activated in cells infected with herpes virus. • Uninfected cells do not phosphorylate acyclovir.
  • 147. Anti-Viral drugs Antiviral spectrum : • Acyclovir: HSV-1( is typically transmitted by oral-to-oral contact and causes infection in or around the mouth (oral herpes), but it can also cause genital herpes), HSV-2 ( is mainly sexually transmitted and causes genital herpes), VZV (chickenpox and herpes zoster (shingles)) • Ganciclovir / Cidofovir : CMV (mononucleosis or hepatitis (liver problem).) • Famciclovir : Herpes genitalis and shingles (painful rash) • Foscarnet : HSV, VZV, CMV, HIV • Penciclovir : Herpes labialis ( rash of the skin and mucous membranes,in particular, the lips)) • Trifluridine : Herpetic keratoconjunctivitis
  • 148. Anti-Viral drugs Pharmacokinetics of Acyclovir : • Oral bioavailability ~ 20-30% • Distribution in all body tissues including CNS • Renal excretion: > 80% • Half lives: 2-5 hours • Administration: Topical, Oral , IV
  • 149. Anti-viral drugs Adverse effects of Acyclovir / Ganciclovir • Nausea, vomiting and diarrhea • Nephrotoxicity - crystalluria, haematuria, renal insufficiency • Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir (a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets)
  • 150. Anti-viral drugs Therapeutic uses : Acyclovir is the drug of choice for: • HSV Genital infections • HSV encephalitis • HSV infections in immunocompromised patient Ganciclovir is the drug of choice for: • CMV retinitis in immunocompromised patient • Prevention of CMV disease in transplant patients
  • 151. Anti-viral drugs Cidofovir : • It is approved for the treatment of CMV retinitis in immunocompromised patients • It is a nucleotide analog of cytosine – no phosphorylation required. • It inhibits viral DNA synthesis • Available for IV, Intravitreal inj, topical • Nephrotoxicity is a major disadvantage.
  • 152. Anti-viral drugs PHARMACOLOGY OF VIDARABINE • Vidarabine is a nucleoside analog. (adenosine) Antiviral spectrum of Vidarabine : HSV-1, HSV-2 and VZV. Its use is limited to HSV keratitis only
  • 153. Anti-viral drugs Vidarabine • The drug is converted to its triphosphate analog which inhibits viral DNA-polymerase. • Oral bioavailability ~ 2% • Administration: Ophthalmic ointment • Used in HSV keratoconjunctivitis in immunocompromised patient. • Anemia and SIADH (Syndrome of inappropriate antidiuretic hormone secretion) are adverse effects.
  • 154. Anti-viral drugs PHARMACOLOGY OF TRIFLURIDINE • Trifluridine is a Pyrimidine nucleoside analogs - inhibits viral DNA synthesis. Antiviral spectrum Trifluridine : • HSV-1, HSV-2 and VZV. • Use is limited to Topical - Ocular HSV Keratitis
  • 155. Anti-viral drugs PHARMACOLOGY OF FOSCARNET • Foscarnet is an inorganic pyrophosphate analog • It directly inhibits viral DNA and RNA - polymerase and viral inverse transcriptase (it does not require phosphorylation for antiviral activity)
  • 156. Anti-viral drugs Foscarnet • HSV-1, HSV-2, VZV, CMV and HIV. • Oral bioavailability ~ 10-20% • Distribution to all tissues including CNS • Administration: IV
  • 157. Anti-viral drugs Adverse effects of Foscarnet • Hypocalcemia and hypomagnesemia (due to chelation of the drug with divalent cations) are common. • Neurotoxicity (headache, hallucinations, seizures) • Nephrotoxicity (acute tubular nephrosis is a condition that causes the lack of oxygen and blood flow to the kidneys, damaging them, interstitial nephritis)
  • 158. Anti-viral drugs Therapeutic uses of Foscarnet • It is an alternative drug for • HSV infections (acyclovir resistant / immunocompromised patient ) • CMV retinitis (ganciclovir resistant / immunocompromised patient )
  • 159. Anti-viral drugs Respiratory viral infections Influenza – • Amantadine / Rimantadine • Oseltamivir / Zanamavir (Neuraminidase inhibitors) RSV (Respiratory syncytial virus) bronchiolitis – • Ribavirin
  • 160. Anti-viral drugs Amantadine and Rimantadine : Influenza (A,B,C,D) • Prevention & Treatment of influenza A • Inhibition of viral uncoating by inhibiting the viral membrane protein M2 OF Influenza A virus • Amantadine has anti- parkinsonian effects.
  • 161.
  • 162. Anti-viral drugs Pharmacokinetics of Amantadine • Oral bioavailability ~ 50-90% • Amantadine cross extensively BBB whereas Rimantadine does not cross extensively . • Administration: Oral
  • 163. Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • Influenza contains an enzyme neuraminidase which is essential for the replication of the virus. • Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell.
  • 164. Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • These are effective against both types of influenza A and B. • Do not interfere with immune response to influenza A vaccine. • Can be used for both prophylaxis and acute treatment.
  • 166. Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir • Oseltamivir is orally administered. • Zanamavir is given intranasal. • Risk of bronchospasm with zanamavir
  • 167. Anti-viral drugs PHARMACOLOGY OF RIBAVIRIN • Ribavirin is a guanosine analog. • Inhibition of RNA polymerase Antiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus
  • 168. Anti-viral drugs Ribavirin : RSV (Respiratory syncytial virus) • Distribution in all body tissues, except CNS • Administration : Oral, IV, Inhalational in RSV. • Anemia and jaundice are adverse effects • Not advised in pregnancy.
  • 169. Anti-viral drugs Therapeutic uses Ribavirin Ribavirin is the drug of choice for: • RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) • Lassa fever Ribavirin is an alternative drug for: • Influenza, parainfluenza, measles virus infection in immunocompromised patients
  • 170. Anti-viral drugs Hepatic Viral infections : • Interferons • Lamivudine – cytosine analog – HBV • Entecavir – guanosine analog – HBV – lamivudine resistance strains • Ribavirin – Hepatitis C (with interferons)
  • 171. Anti-viral drugs Interferons Interferons (IFNs) are natural proteins produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. • Antiviral, immune modulating (modify immune response) and anti-proliferative actions (inhibit growth) • Three classes of interferons – α , β, γ
  • 172.
  • 173. Interferons • α and β interferons are produced by all the cells in response to viral infections • γ interferons are produced only by T lymphocyte (a lymphocyte of a type produced or processed by the thymus gland and actively participating in the immune response) and NK (a type of white blood cell) cells in response to cytokines – immune regulating effects • γ has less anti-viral activity compared to α and β interferons
  • 174.
  • 175. Mechanism of action of Interferons : • Induction of the following enzymes: 1) a protein kinase which inhibits protein synthesis 2) an oligo-adenylate synthase which leads to degradation of viral mRNA 3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation
  • 176. Anti-viral drugs Antiviral spectrum : Interferon α • Includes HBV, HCV and HPV (Human papillomavirus). • Anti-proliferative actions may inhibit the growth of certain cancers - like Kaposi sarcoma (disease in which cancer cells are found in the skin or mucous membranes that line the gastrointestinal (GI) tract, from mouth to anus, including the stomach and intestines.) and hairy cell leukemia (a type of cancer in which the bone marrow makes too many lymphocytes).
  • 177. Anti-viral drugs Pharmacokinetics : Interferons • Oral bioavailability: < 1% • Administered Intralesionally, S.C, and I.V • Distribution in all body tissues, except CNS and eye. • Half lives: 1-4 hours
  • 178. Anti-viral drugs Adverse effects of Interferons • Acute flu-like syndrome (fever, headache) • Bone marrow suppression (granulocytopenia, thrombocytopenia) • Neurotoxicity (confusion, seizures) • Cardiotoxicity - arrhythmia • Impairment of fertility
  • 179. Anti-viral drugs Therapeutic uses Interferons • Chronic hepatitis B and C (complete disappearance is seen in 30%). • HZV infection (Herpes zoster, also known as shingles) in cancer patients (to prevent the dissemination of the infection) • CMV infections in renal transplant patients • Condylomata acuminata (given by intralesional injection). Complete clearance is seen ~ 50%. • Hairy cell leukemia (in combination with zidovudine) • AIDS related Kaposi’s sarcoma
  • 180. Virus Diseases Drug(s) of choice Alternative drugs FLU A Influenza Amantadine Rimantadine RSV Pneumonia, bronchiolitis Ribavirin (aerosol) HSV Genital herpes Acyclovir Foscarnet Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine Encephalitis Acyclovir Neonatal HSV infection Acyclovir Vidarabine Herpes infections in immuno- compromised host Acyclovir Foscarnet
  • 181. VZV In normal host No therapy In immunocompro- mised host, or during pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HIV AIDS HIV antibody positive with CD4 count < 500/mm3 Zidovudine ± protease inhibitors Didanosine, Stavudine HBV HCV Hepatitis B, C Interferons
  • 183. Introduction • Human fungal infection have increased dramatically in incidence and severity in recent years due to mainly advances in surgery, cancer treatment and critical care accompained by increase in use of broad spectrum antimicrobial and HIV. • Infectious diseases caused by fungi are called mycoses and they are often chronic in nature. • Some mycotic infections are superficial and some involve skin but fungi may penetrate into skin causing sub cutaneous infections. • The fungal infection that are most difficult to treat are systemic mycoses, which are often life threatening.
  • 184. • Unlike bacteria, fungi are eukaryotic (Nucleus). They have rigid cell walls composed of largely of chitin rather than peptidoglycan. • The fungal cell membrane contain ergosterol rather than cholesterol found in mammalian membrane. These Chemical characteristic are in targeting chemotherapeutic agents against fungal infections. • Fungal infections are generally resistant to antibiotics used in treatment of bacterial infection and conversely bacteria are resistant to antifungal agents.
  • 185.
  • 186. Classification of Antifungal Drugs 1. Drugs for Sub cutaneous and systemic mycoses : • Amphotericin B • Andidulafungin • Caspofungin • Fluconazole • Flucocytosine • Itraconazole • Ketoconazole • Micafungin • Posaconazole • voriconazole Mycoses that cause superficial infections of the epidermis, hair, and nails, are called cutaneous mycoses. Mycoses that penetrate the epidermis and the dermis to infect deeper tissues are called subcutaneous mycoses.
  • 187. Classification of Antifungal Drugs 2. Drugs for cutaneous Mycoses: • Butenafine • Clotrimazole • Ciclopirox • Ecoconazole • Greisofulvin • Micoconazole • Naftifine • Nystatin • Oxiconazole • Sertaconazole • Sulconazole • Terbinafine • Terconazole • Tioconazole • tolnaftate
  • 188. Drugs for subcutaneous and systemic mycotic infection
  • 189. 1. Amphotericin B • Amphotericin B is a naturally occurring polyene macrolide antibiotic produced by streptomyces nodosus. • Inspite of its toxicity, Amphotericin B is a drug of choice for treatment of systemic mycoses.
  • 190. Mechanism of action • Several amphotericin B molecule bind to ergosterol in plasma membrane of sensitive fungal cell they form pores (channels) that require hydrophobic interactions between lipophilic segment of polyene antibiotic and the sterol. • The protein disrupts membrane function, allowing electrolytes ( particularly postassium) and small molecules to leak from cell, resulting in cell death.
  • 191. PHARMACOLOGY OF AMPHOTERICIN B Chemistry -Amphotericin B is a polyene antibiotic (polyene: containing many double bonds) Mechanism of action -Binding to ergosterol present in the membranes of fungal cells  Formation of “pores” in the membrane  Leaking of small molecules (mainly K+) from the cells -The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
  • 192. Antifungal Spectrum Amphotericin B is either fungicidal or fungistatic depending upon the on the organism and concentration of drug. It is effective against a wide range of fungi including: • Candida albican (is a naturally occurring fungus that lives on your body) • Histoplama capsulatum (is an environmental dimorphic fungus) • Cryptococcus neroforman (fungus that lives in the environment throughout the world.) • Aspergillus (Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide.)
  • 193. Pharmacokinetic • Amphotericin B is administered by slow, Iv infusion. • The most dangerous intrathecal route is chosen for treatment of meningitis caused by fungi that are sensitive to drug • Amphotericin B has also been formulated with a variety of artificial lipids that form liposome • Amphotericin B is extensively bound to plasma proteins and is distributed throughout the body becoming highly bound tissue.
  • 194. • Low level of drug and its metabolite appear in urine over a long period of time and some are also eliminated via bile. • To avoid nephrotoxicity, alternatives including sodium loading with infusion of normal saline and lipid base amphotericin B products are used.
  • 195. Adverse Effects • Amphotericin B has low therapeutic index. 1. Fever and Chills: These occurs most commonly 1 to 3 hr after starting IV administration but they are usually subside with repeated administration 2. Renal Impairment: Despite the low level of drug excrete in urine patient may exhibit a decrease in glomerular filtration rate. Creatanine clearance can drop and K and Mg can are lost.
  • 196. 3. Hypotension: A shock life fall in blood pressure accompained by hypokalemia may occur, require potassium supplimentation 4. Anemia can occur due to suppression of erythropoietin production 5. Neurologic Effects can be seen with intrathecal administration of drug. 6. Thrombophlebitis (blocking due To clots)
  • 197. Liposomal preparations of amphotericin B • Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing : • A. Nephrotoxicity • B. Infusion toxicity • Also, more effective • More expensive
  • 198. 2. Flucytosine (5-FC) • Flucytosine is a synthetic pyrimidine antimetabolite (inhibit metabolism) • that is often use in combination with amphotericin B.
  • 199. Mechanism of action • 5 F-C (flucytosine) is taken by fungal cells via enzyme cytosine premase • It is converted intracellulary first to 5 FU and then to 5- fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP) which inhibits DNA & RNA synthesis respectively • Human cells are unable to convert parent drug into its active metabolite
  • 200.
  • 201.
  • 202.
  • 203.
  • 204. 3.Ketoconazole (AZOLE) • Ketoconazole was first orally active azole available for treatment of systemic mycoses.
  • 205. Mechanism of action • Azoles are predominantly fungi static. • They inhibit C-14 α-demethylase ( a cytochrome P450 enzyme) thereby blocking the demethylation of lanosterol to ergosterol. The principle sterol of fungal membrane. • This inhibition disrupts membrane structure and function which in turn inhibits fungal cell growth. • Azoles are relatively Non-toxic • Most common adverse reaction is relatively minor gastrointestinal upset.
  • 206. Drug Interaction & Contraindication • All azoles have been reported to cause abnormalities in liver enzyme. • By inhibiting cypP450, ketoconazole can potentiate the toxicities of other drugs such as cyclosporine and phenytoin and warfarin • Ketoconazole and amphotericin B should not be use together because the decrease in ergosterol in fungal membrane reduce the fungicidal action of amphotericin B.
  • 207. Contraindication • Ketoconazole is teratogenicity in animals and is should not be given in pregnancy
  • 208. Other Drugs Are: • Fluconazole • Itraconazole • Voriconazole • Posaconazole
  • 209. Echinocandins • Echinocandins are antifungal drugs that inhibit the synthesis of glucan in cell wall via inhibition of all enzyme 1,3 ß glucan synthase. • 3 drugs from this class are currently used clinically: – Caspofungin – Micafungin – Anidulafungin
  • 210. Caspofungin • It is the first member of echocandins class of antifungal drugs. • Caspofungin has activity against aspergillus and most candida species including those species that are resistant to azoles.
  • 211. Adverse Effects include • Fever • Rash • Nausea • Phlebitis (inflammation of the walls of a vein) • Flushing occur due to release of histamine from mast cell
  • 212. Drugs for cutaneous mycotic Infection • Mold like fungi that cause cutaneous skin infections are called dermatophytes or tinea. • These tinea are classified by the site of their infection such as tinea pedis, which refers to an infection of feets.
  • 213. Squalene Epioxidase Inhibitor • These agents act by inhibiting squalene epioxide, resulting in blocking of biosynthesis of ergosterol, an essential component of fungal cell membrane. Drugs: 1. Terbinafine 2. Naftifine 3. Butenafine
  • 214. Terbinafine • Oral terbinafine is a drug of choice for treating dermatophytoses especially onychomycoses (Nail infection) • Terbinafine hydrochloride, also known under the trade name Lamisil,is a synthetic allylamine antifungal developed by Novartis. It is highly hydrophobic in nature and tends to accumulate in skin, nails, and fatty tissues.
  • 215. Mechanism of Action • Like Azole drugs, it interfere with ergosterol biosynthesis but rather than interacting with P450 system, terbinafine inhibits the fungal enzyme squalene epioxide. This leads to accumulation of sterol squalene which is toxic to organism. • Squalene epioxide is the enzyme that govern the conversion of squalene into ergosterol ( the major component of fungal cell membrane). If squalene epioxide is inhibited it will not converted to ergosterol and hence squalene starts accumulating in fungal cell, which leads to fungal cell death.
  • 216. Antifungal Spectrum • The drug is primarily fungicidal. Topical terbinafie 1% cream and soultion are used to treat tinea pedis, tinea corporis ( Scalp), and tinea cruris ( groin area).
  • 217. Griseofulvin • Griseofulvin has been largely replaced by oral terbinafine for the treatment of dermatophytic infections of the nails, although it is still used for ring worm and dermatophytosis of the skin and hair.
  • 218. Mechanism of action • Griseofulvin mechanism of action at cellular level is unclear but it is deposited in newly forming skin where it binds to keratin, protecting skin from new infection. • Since its action is to prevent infection of these new skin structures, it must be administered for 2-6 weeks for skin and hair infection to allow replacement of infected keratin by resistant structure. • Nail infection may require therapy for months to allow regrowth of protected nail.
  • 219.
  • 220.
  • 221.
  • 222. Other drugs are: • Nystatin ( binds to ergosterol in the fungal cell membrane, which leads to the formation of pores, ion leakage and ultimately fungal cell death) • Imidazole include ( Butoconazole, Clotrimazole, Oxiconazole, Ecoconazole etc),work as azole • Ciclopirox (Ciclopirox inhibit transport of essential elements thus result in Disruption of RNA , DNA and protein synthesis in fungal cell) • Tolnaftate (inhibit ergosterol synthesis)
  • 223. ANTHELMINTIC DRUGS Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye.
  • 224. Introduction to anthelmintics • Anthelmintics are drugs that are used to treat infections with parasitic worms. This includes both flat worms, e.g., flukes and tapeworms and round worms, i.e., nematodes.
  • 225. 225 INTRODUCTION • Humans are the primary hosts for the most of helminthic infections. • Most worms produce in human sexually by producing eggs and larvae (The larva is a worm-like creature, which emerges from an egg.) • These pass out of body and infect the secondary host • These invade humans via skin or GIT.
  • 226. 226 Types (clinical) 1. Worms live in hosts alimentary canal. E.g Tapeworm 2. Worms or larvae live in other tissues of host body like muscles , viscera , menninges , lungs, subcutaneous tissues. E.g: Taenia solium
  • 228. Drugs for the treatment of Nematodes • Nematodes are elongated roundworms that posses a complete digestion system including both a mouth and an anus. • They cause infection of intestine as well as the blood and tissue.
  • 229. 229 MEBENDAZOLE(Vermox) • it is a synthetic benzimidazole • it has wider spectrum Mechanism of action: It inhibits microtubule synthesis in nematodes that irreversibly impairs glucose uptake. Intestinal parasites are immobilized and die slowy. It kills hook worm, pin worm , ascariasis and trichuris eggs.
  • 230. 230 Pharmacokinetics: • less than 10% of orally administered drug is absorbed • Absorption increases with fatty meal. • Absorbed drug is 90 % protein bound • It is converted to inactive metabolites rapidly in liver. • It has half life of 2-6 hours • It is primarily excreted in urine.
  • 231. 231 Thiabendazole • it is benzimidazole • it is chelating agent and form stable complexes with metals including iron, but does not bind with calcium. • it is rapidly absorbed • it has half life of 1.2 hrs • It is completely metabolized in liver and 90% is excreted in urine • it can also get absorbed through skin
  • 232. 232 Thiabendazole Mechanism of action: similar to other benzimidazoles (It inhibits microtubule synthesis ). It is ovicidal for some parasites. Adverse reactions and contraindications: • It is more toxic than other benzamidazoles • GI disturbances • Pruritus ,headache, drowsiness , psychoneurotic symptoms (anxiety, depression, or other feelings of unhappiness ). • Irreversible live failure. • Fatal Steven –Johnson syndrome(inflammation of skin) • Not used in children below 15 kg weight. pregnancy, hepatic and renal diseases.
  • 233. 233 PYRANTEL PAMOATE • It is a broad specturm anthelmintic. Pharmacokinetics: • It is poorly absorbed orally , • Half of the drug is excreted unchanged in the feces. Mechanism of action: • It is a depolrazing neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinestrase leads to paralizes of worms. The paralyzed worm is then expelled from the host intestinal tract.
  • 234. 234 Pyrental Pamoate Adverse Effects: • Infrequent mild transient GI disturbance • drowsiness , headache ,insomnia. • Rash ,fever Contraindications: • Should not be used in liver diseases. • Pregnancy • and child under 2 years of age
  • 235. Drugs for the treatment of Trematodes • The trematodes (flukes) are leaf shaped flatworms that are generally characterized by the tissues they infect. • For example, they maybe categorized as liver, lung, intestinal or blood flukes.
  • 236. Praziquantel • Agent of choice for treatment of all forms of schistosomiasis and other trematode infections. • Rapidly absorbed after oral administration and distributes into CSF. • High level occur in bile • Drug is excreted through urine and bile. • Contraindicated for occular cysticercosis because of destruction of the organism in the eye may damage the organ.
  • 237. Mechanism of action • The mode of action is not exactly known at present, but experimental evidence indicates praziquantel increases the permeability of the membranes of schistosome cells towards calcium ions. • The drug thereby induces contraction of the parasites, resulting in paralysis in the contracted state. • The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction (phagocytosis).
  • 238. Drugs for the treatment of Cestodes • The cestodes or true tapeworms typically have a flat, segmented body and attach to the hosts intestine. • Like trematodes the tapeworms lack a mouth and a digestive tract throughout their life cycle.
  • 239. 239 NICLOSAMIDE • It is a useful drug for treatment of tape worm (cestodes) • Mechanism of action: • Adult worm is rapidly killed by inhibition of mitochondiral oxidative phosphorylation of adenosine diphosphate or stimulation of ATPase activity. Pharmacokinetics: • It is poorly absorbed from gut • Neither drug nor its metabolites are found in blood or urine
  • 240. 240 Niclosamide Adverse effects: • Mild ,infrequent and transitory GI disturbance • Alcohol consumption should be avoided • not indicated in children under 2 years of age.
  • 241. 241 ALBENDAZOLE • It is a broad spectrum • It is a drug of choice (primary therapeutic application) for treatment of hydatid disease or cystecercosis, it is also used for the treatment of intestinal nematodes like ascariasis ,tricurasis and strongyloidiasis , pinworm, hookworm
  • 242. 242 Albendazole Mechanism of action: It inhibits microtubule synthesis in nematodes(intestinal round worms) that irreversibly impairs glucose uptake, intestinal parasites are immobilized and die slowly. • It is larvicidal in hydatid ,cysticercosis , ascariasis and hook worm infection. • Also ovicidal in ascariasis , ancyclostomiasis(hookworm) , tricurasis
  • 243. 243 Pharmacokinetics (Albendazole) • It is benzimidazole • it is adminstered orally , and absorbed erratically (unpredictable) , absorption can be increased with fatty meal • It is metabolized in the liver rapidly to active metabolite albendazole sulphoxide
  • 244. 244 Pharmacokinetics (Albendazole) • It has a plasma half life of 8-12 hours • Sulphoxide is mostly protein bound , distributes well to tissues and enters bile, csf, hydated cyst • Metabolites are excreted in urine
  • 245. 245 Clinical uses (albendazole) • used on empty stomach when used against intraluminal parasites but with fatty meal when against tissue parasites. • In ascariasis ,tricurasis ,hookworm, pin worm infection : children under 2 years 400 mg orally as a single dose repeated for 2-3 days in heavy ascariasis ,repeated after 2-3 wks for pin worm 2. Hydated diseases: drug of choice ,400 mg twice with meals for 1 month or longer.
  • 246. 246 Albendazole 3. Neurocysticercosis: It is controversial as it has not proved superior to corticosteroid alone. It is used along with cotricosteroid to decrease the inflammation caused by dying organism and it also reduces the duration of course i.e. 400 mg twice daily for 21 days 4. Other infections: Drug of choice in cutaneous and visceral larvea migrans , intestinal cappillariasis and others
  • 247. 247 Albendazole Adverse effects: • In short term: use no significant adverse effects. • In long term use : as used in hydatid cyst and cysticercosis, abdominal distress, headache ,fever , fatigue, alopecia , increased liver enzymes , pancytopenia. Blood counts and LFT should be followed. • Not given during pregnancy and in hypersensitive people.
  • 249. 249 INTESTINAL WORMS A) INTESTINAL ROUND WORMS (NEMATODES) • Ascaris lumbbricods (common round worm) • Enterobius vermicularis (pin worm) • Trichuris trichuria ( whip worm) • Strongyloids stercoralis ( thread worm) • Ankylostoma dudenale (hook worm)
  • 250. 250 Ascaris lumbricoids ( common round worm)
  • 255. 255 1. Alimentary canal(intestinal tape worms) B) TAPE WORMS (CESTODES) • Taenia saginata(Beaf) , • Taenia solium(Pork),Hymenolepis nana(Dwarf) ,diphylobothrium latum(Fish) • Humans become infected by eating raw or under cooked meat containing larvae of infected cattle or pig which has encysted in the animal muscle tissue.
  • 256. 256 Cestodes • In some conditions this larvae may develop in humans resulting cysticercosis (i.e. larvae gets encysted in the muscle and viscera or more seriously in the brain or eye.) • both adult worm and larvae can be present in the same host.
  • 259. 259 2. TISSUE WORMS A.TREMATODES(Schisotomes)OR FLUKES(leaf like) • Schistosoma haematobium • Schistosoma Japonicum • Schistosoma mansoni (These cause SCHISTASOMIASIS) also called (BILHARZIA) means disease of blood vessels. Adult worms of both sex live and mate in veins or venules of the gut wall or the bladder, eggs pass into the bladder or gut and produce inflammation of these organs , resulting in haematuria or loss of blood in feces.
  • 260. • Paragonimus westermani (lung fluke) disease is caused by eating raw crab or fish , larvae move from intestine to blood and settle in lungs • Clonorchis sinensis(liver fluke) disease is caused by eating raw fish and worm settle in the biliary tract 260
  • 261. 261 Tissue worms • B. TISSUE ROUND WORMS Trichnella spiralis. Dracunulus medinensis (guinea worm)larva migrate from intestine to tissue of leg or foot and protrude out by making ulcer
  • 262. FILARIAE includes Wuchereria bancrofti Loa loa Onchocerera volvulus Brugia malayi 262
  • 264. 264
  • 266. Introduction • Protozoal infections are common among people in underdeveloped tropical and subtropical countries, where sanitary conditions, hygienic practices and control of vectors for transmission are inadequate. • Most antiprotozoal agents have not proved to be safe for pregnant patients.
  • 267. Protozoal infections 1. Amebiasis 2. Malaria 3. Giardiasis 4. Leshmaniasis 5. Toxoplasmosis 6. Trypanosomiasis
  • 268. Protozoal infections 1. Difficult to be treated than bacterial infections. 2. Protozoal cells (Eukaryotes) have metabolic processes closer to human host than prokaryotic bacterial pathogens. 3. Many of antiprotozoal drugs cause toxic effects on the host. 4. Cells with high metabolic processes in the host are susceptible. 5. Examples: bone marrow stem, renal tubular cells, intestinal & neuronal cells. 6. Antiprotozoal are not safe during pregnancy.
  • 269. Anti Protozoal Drugs 1. Amebiasis ( chloroquine, Dehydroemetine, emetine, iodoquinol, metronidazole, paromomysin, tinidazole) 2. Malaria (Artemisinin, chloroquine, mefloquine, primaquine, pyrimethamine, quinine/quinidine) 3. Trypanosomiasis (Benznidazole, Melarsoprol, Nifurtimox, pentamidine, suramin ) 4. Leishmaniasis (Sodium stibgluconate) 5. Toxoplasmosis (Pyrimethamine) 6. Giardiasis (Metronidazole, nitazoxanide, tinidazole)
  • 271. Amebiasis Amebiasis is a protozoal infection of the intestinal tract that occurs due to ingestion of foods or water contaminated with Entameba Histolytica cysts
  • 272. LIFE CYCLE Entamoeba histolytica exists in two forms: 1. Cysts (infective): • can survive outside the human body. • transform to trophozoites. 2. Trophozoites (non-infective; invasive): • Can reproduce • They may feed on intestinal bacteria or invade and ulcerate wall of large intestine, and may migrate to liver or other tissues. • transform to cysts which are excreted in feces.
  • 273. Life Cycle 1. Cysts ingestion. 2. Formation of trophozoites 3. Penetration of intestinal wall 4. Multiplication of trophozoites within colon wall. 5. Systemic invasion. 6. Cyst formation in rectum and excretion in feces.
  • 275. ANTIAMEBIC DRUGS ▪ Luminal Amebicides ▪ Tissue or systemic amebicides ▪ Mixed Amebicides
  • 276. LUMEN AMOEBICIDES • Acts on the parasites in the lumen of the bowl. • used for treatment of asymptomatic amebiasis. Include • Diloxanide Furoate • Iodoquinol Antibiotics - Paromomycin - Tetracyclines - Erythromycin
  • 277.  acts on the intestinal wall and liver (or any other extra-intestinal tissue).  Used for treatment of systemic form of the disease (intestinal wall infection or liver abscesses).  Emetine  Dehydroemetine  Chloroquine (liver only) Tissue Amoebicides (systemic)
  • 278. Mixed amoebicides Effective against both luminal and systemic forms of the disease. Although luminal concentration is too low for single drug – treatment. • Metronidazol • Tinidazole
  • 279. Drugs
  • 280. METRONIDAZOLE • Mixed amoebicide. • Drug of choice for intestinal & extraintestinal amoebiasis. • Acts on trophozoites. • Has no effect on cysts. • Nitro group of metronidazole is reduced by protozoan leading to cytotoxic reduced product that binds to DNA and proteins resulting into parasite death.
  • 281. Pharmacokinetics • Given orally or IV. • Absorption is rapid and complete. ▪ Due to rapid absorption from GIT, not reliably effective against luminal parasites. • Wide distribution to all tissues and body fluids (CSF, saliva, milk). • Plasma protein binding is low ( < 20%). • Plasma half life is 8 h
  • 282. Pharmacokinetics • Metabolized in liver by mixed function oxidase followed by glucouroidation. • Excreted in urine as unchanged drug plus metabolites. • Clearance is decreased in liver impairment. Tinidazole has longer duration, simpler dosing regimen, less toxicity, than metronidazole, but is equally active.
  • 283. Adverse effects 1. GIT: • Nausea • Vomiting • Dry mouth • Metallic taste • Diarrhoea • Oral Thrush (Moniliasis, yeast infection).
  • 284. Adverse effects 2. CNS: Neurotoxicological effect – Insomnia, dizziness – peripheral neuropathy, paresthesia ( burning or prickling sensation) – Encphalopathy (disease of the brain that alters brain function or structure), convulsion ( IV infusion, rare). 3. Dysuria (Painful urination), dark urine. 4. Neutropenia 5. Disulfiram-like effect if taken with alcohol. nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort
  • 285. Disulfiram like -effect When metronidazole is given with alcohol abdominal distress, nausea, vomiting, flushing, or headache, tachycardia, hyperventilation alcohol aldehyde dehydrogenase dehydrogenase Ethanol Acetaldehyde Acetate
  • 286. EMETINE AND DEHYDROEMETINE Chemistry:  Emetine hydrochloride is a plant alkaloid (organic nitrogen-containing bases) derived from ipeca.  Dehydroemetine is a synthetic analogue Pharmacokinetics:  Erratic oral absorption.  Given preferably subcutaneously but could be given by IM.  Plasma half life is 5 days.
  • 287. EMETINE • Concentrated in Liver, Lungs, Spleen, Kidney, Cardiac muscle and Intestinal wall. • Metabolized & Excreted slowly via kidney so it has a cumulative effect. • Trace amounts could be detected in urine 1-2 month after last dose. • Should not be used for more than 10 days (usually 3-5 days).
  • 288. Mechanism • Act on tissue trophozoites causing irreversible block of protein synthesis.
  • 289. Adverse Effects • Dehydroemetine is less toxic than emetine • pain at site of injection, abcesses ( painful collection of pus). GIT: nausea, vomiting, diarrhoea. Neuromuscular weakness Serious toxicities: cardiotoxicity - cardiac arrhythmias, - Hypotension - heart failure
  • 290. Chloroquine • Antiamebic drug • Antimalarial drug • Used in combination with metronidazole and luminal amebicide for amebic liver diseases.
  • 291. Luminal amoebicides • acts on the luminal parasites like Entamoeba histolytica (Amebae) Balantidium coli (Ciliates). • used for treatment of asymptomatic amebiasis. Include Diloxanide Furoate • Iodoquinol • Antibiotics - Paromomycin - Tetracyclines - Erythromycin
  • 292. Diloxanide furoate Chemistry • Ester of diloxanide + furoic acid . Pharmacokinetics • Given orally. • Split in the intestine, most of diloxanide is absorbed, conjugated to form a glucoronide which is excreted in urine (90%). • The unabsorbed diloxanide is the amoebicidal agent (10%).
  • 293. Pharmacodynamics: • Unkown mechanism of action • Direct amoebicidal action against luminal forms.
  • 294. Therapeutic Uses • Drug of choice for asymptomatic intestinal infection. • For eradication of infection given along with all forms of amebiasis. • Dose: 500 mg three times/day for 10 days.
  • 295. Adverse Effects • Flatulence • Nausea, vomiting, abdominal cramps. • No serious adverse effects Contraindications: - Pregnancy - Children (less than 2 years).
  • 296. Paromomycin Sulphate • Aminoglycoside, not absorbed. • Effective against luminal forms of ameba Mechanism of action • Direct amebicidal action (causes leakage by its action on cell membrane of parasite). • Indirect killing of bacterial flora essential for proliferation of pathogenic amoebae.
  • 297. Kinetics • Orally • Not significantly absorbed from the GIT • Small amount absorbed is excreted unchanged in urine (may accumulate with renal insufficiency).
  • 298. Adverse effects • Gastrointestinal distress and diarrhea. Precautions • Severe renal disease • patients with GIT ulceration
  • 299. Tetracyclines • Very weak direct amoebicidal action. • Mainly act indirectly on bacterial flora. • Used in severe cases of amoebic dysentery not responding to metronidazole combined with dehydroemetine.
  • 300. HALOGENATED HYDROXYQUINOLINES • Iodoquinol Mechanism of action • Unknown • Effective against organisms in GIT only Not intestinal wall or liver. Pharmacokinetics • Absorption is poor, excreted in feces. • 10% enter circulation, excreted as glucouronide in urine. • Half life is 11-14 h
  • 301. Uses • lumen amoebicide. • For eradication of infection given along with tissue amoebicide (metronidazole).
  • 302. Adverse Effects • Peripheral neuropathy including optic neuritis • GIT: Nausea, vomiting, diarrhoea. • Enlargement of the thyroid gland. • Agranulocytosis (low number of granulocytes). • Iodine sensitivity. • interference with thyroid function tests (increase protein-bound serum iodine, decrease in measured 131I uptake).
  • 303. Contraindications • Optic neuropathy • Thyroid disease • Sensitivity to iodine • Severe liver disease • Severe kidney disease • discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever)
  • 305. • Anti Malarials: The word "malaria" actually derives from the Italian for "bad air"-- the mal'aria associated with marshes and swamps. • Malaria is a febrile (related to fever) disease caused by a single-celled parasite known as a sporozoan (able to form spore-like cells, from which they get their name) and transmitted by a female mosquitoes of the genus Anopheles. • This sporozoan belongs to the genus Plasmodium, and the five species that infect humans are: • Plasmodium falciparum • Plasmodium malariae • Plasmodium ovale • Plasmodium vivax • Plasmodium knowlesi
  • 306. • Signs and symptoms: • High grade fever • Headache • Spleenomegaly • Sweating and chills • Muscles aches • Nausea, vomitting and diarrhoea • Anemia etc
  • 307. • Life cycle plasmodium: • Antimalarials: Agents used for treatment and prophylaxis of malaria.
  • 308. PARASITE LIFE CYCLE An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.
  • 309. • Classification: 1) 4-aminoquinolines: 5) Quinoline methanol • chloroquine . Mefloquine • hydroxy chloroquine 6) Biguanides • Amodiaquine . Proguanil 2) 8-aminoquinolines: . Chlorproguanil • Pamaquine 7) Sulfonamides and sulfones • Primaquine . Sulfadoxine, 3) Cinchona alkaloids: . Sulfamethopyrazine • Quinine 8) Sesquiterpene lactones • Quinidine . Artemether • Cinchonine . Artesunate • Cinchonidine 9) Naphthoquinone 4) Diaminopyrimidines: . Atorvaquone • Pyrimethamine 10) Combinations . sulfadoxine and pyrimethamine (chloroquine resistant P.falciparum) . sulfadoxine + pyrimethamine + Chloroquine
  • 310. DRUG CLASSIFICATION Tissue schizonticides: eliminate developing or dormant liver forms; Blood schizonticides : act on erythrocytic parasites; Gametocides : kill sexual stages and prevent transmission to mosquitoes. Radical cure: eliminate both hepatic and erythrocytic stages. Not available.
  • 312. PRIMAQUINE Hepatic stages of all human malaria parasites. Chemoprophylaxis against all malarial species. It is the only available agent active against the dormant stages of p vivax and p ovale. Gametocidal against the 4 human malaria species. Acts against erythrocytic stage parasites, but this activity is too weak to play an important role. MOA: is unknown.
  • 313. MECHANISM OF ACTION Mechanism is not completely understood. Metabolites of primaquine are believed to act as oxidant that are responsible for schizonticidal actions as well as for the hemolysis.
  • 314. ADVERSE EFFECTS Generally well tolerated. • GI disturbance, Headache •Leukopenia, Agranulocytosis, •Cardiac Arrhythmias, Hemolysis It is never given parenterally because it may induce marked hypotension. It should be avoided in pregnancy because the fetus is relatively G6PD(glucose-6-phosphate dehydrogenase)-deficient and thus at risk of hemolysis.
  • 316. CHLOROQUINE  For treatment and chemoprophylaxis since the 1940s,(drug resistance). Oral use Antimalarial Action: Highly effective blood schizonticide.  Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum.  Not active against liver stage parasites.
  • 317. MECHANISM OF ACTION Acts by : concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme.
  • 318. CLINICAL USES Drug of choice in the treatment of nonfalciparum and sensitive falciparum malaria.  It is still used to treat falciparum : safety, low cost, antipyretic properties, and partial activity. Does not eliminate dormant liver forms of P vivax and P ovale, and for that reason Primaquine must be added for the radical cure of these species.
  • 319. ADVERSE EFFECTS • Usually very well tolerated • Pruritus, GI disturbance, headache, malaise, blurring of vision, and urticaria • Rare : hemolysis in G6PD-deficient persons, impaired hearing, agranulocytosis, alopecia, bleaching of hair, hypotension, • Large IM injections or rapid IV infusions : severe hypotension and respiratory and cardiac arrest.
  • 320. Mefloquine Used in chloroquine-resistant strains of P falciparum and other species. Is chemically related to quinine. Can only be given orally because severe local irritation occurs with parenteral use. Has strong blood schizonticidal activity against P falciparum and P vivax, it is not active against hepatic stages or gametocytes. MOA: The mechanism of action of mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects..
  • 321. QUININE & QUINIDINE • First-line therapies for falciparum malaria. • Oral administration. • Higher plasma levels and half-life in infected persons than in healthy controls, but toxicity is not increased, apparently because of increased protein binding. • MOA: is unknown,
  • 322. Antimalarial action  Is rapid-acting, highly effective blood schizonticide against the 4 species of human malaria parasites.  Gametocidal against p vivax and p ovale but not p falciparum  Not active against liver stage parasites.
  • 323. ARTEMISININ & ITS DERIVATIVES Artemisinin: used orally. Analogs are:  Artesunate (water-soluble; oral, IM, IV and rectally), Artemether (lipid-soluble; oral, IM, and rectally), Dihydroartemisinin (water-soluble; oral). They are very rapidly acting blood schizonticides against all human malaria parasites, no effect on hepatic stages.
  • 324. MOA The parasite when it infects a RBC, it consumes Hb within its digestive vacuole, liberating free heme, The iron in heme interacts with Artemisinin producing reactive oxygen radicals which damage the parasite leading to its death  Or inhibition of a parasite calcium transporter. Artemisinin-based combination therapy is now the standard for treatment of uncomplicated falciparum malaria in nearly all areas endemic for falciparum malaria. GI disturbance, dizziness, neutropenia, anemia, hemolysis, elevated liver enzymes, allergic reactions.
  • 325. INHIBITORS OF FOLATE SYNTHESIS Pyrimethamine ,Proguanil ( Blood Schizonticide and Sporozoite) •Used in combination regimens, in the treatment and prevention of malaria. •Slowly but adequately absorbed from the GIT. Fansidar, a fixed combination of the sulfonamide sulfadoxine and pyrimethamine . Act slowly against erythrocytic forms of susceptible strains of all human malaria species. Proguanil also has some activity against hepatic forms. Neither drug is adequately gametocidal or effective against the persistent liver stages of p vivax or p ovale.
  • 326. MECHANISM OF ACTION Selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. : GI Symptoms, Skin Rashes, Itching. Proguanil: Mouth Ulcers, Alopecia . Proguanil , Fansidar are considered safe in pregnancy
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