Pharmacuetical Chemistry 2 Midterm

Inhibitors of Bacterial Cell Inhibitors of Bacterial Cell Wall SynthesisWall Synthesis

Inhibitors of Bacterial Cell Wall SynthesisInhibitors of Bacterial Cell Wall Synthesis

I.I. Beta Lactam drugs—because of their unique 4 Beta Lactam drugs—because of their unique 4 membered Beta LACTAM ring membered Beta LACTAM ring

II.II. Non Beta Lactam drugs.Non Beta Lactam drugs.

Inhibitors of Bacterial Cell Wall SynthesisInhibitors of Bacterial Cell Wall Synthesisor Membrane-active drugsor Membrane-active drugs

I.I. Beta Lactam drugs Beta Lactam drugs

II.II. Non Beta Lactam drugsNon Beta Lactam drugs

I. Beta Lactam drugsI. Beta Lactam drugs

a.a. PenicillinsPenicillins

b.b. Cephalosporins & CephamycinsCephalosporins & Cephamycins

c.c. MonobactamMonobactam --- Aztreonam --- Aztreonam


d. Beta lactamase inhibitors d. Beta lactamase inhibitors Sulbactam Sodium Sulbactam Sodium Tazobactam SodiumTazobactam Sodium Clavulanate potassium.Clavulanate potassium.

e. Carbapenemse. Carbapenems Ertapenem Ertapenem Imipenem Imipenem MeropenemMeropenem


II.II. Non-Beta Lactam drugsNon-Beta Lactam drugsa.a. VancomycinVancomycin

b.b. TeicoplaninTeicoplanin

c.c. DaptomycinDaptomycin

d.d. FosfomycinFosfomycin

e.e. BacitracinBacitracin

f.f. CycloserineCycloserine

PENICILLINSPENICILLINS

PENICILLINSPENICILLINS

Constitute one of the most important primitive groups of Constitute one of the most important primitive groups of antibiotics that are still being widely used for the treatment & antibiotics that are still being widely used for the treatment & prophylaxis of infections caused by susceptible micro-prophylaxis of infections caused by susceptible micro-organismsorganismsHigh margin of safety & lack organ toxicityHigh margin of safety & lack organ toxicityAcute anaphylaxis – imp AE; needing immediate attentionAcute anaphylaxis – imp AE; needing immediate attentionMajor antibiotics and new derivatives of the basic penicillin Major antibiotics and new derivatives of the basic penicillin nucleus still are being producednucleus still are being producedMany of these have unique advantages such that members of Many of these have unique advantages such that members of this group of antibiotics are currently the drugs of choice for a this group of antibiotics are currently the drugs of choice for a large number of infectious diseases. large number of infectious diseases.

PENICILLINS - HISTORYPENICILLINS - HISTORY

Discovered in 1928 by Alexander Fleming Discovered in 1928 by Alexander Fleming while studying while studying StaphylococcusStaphylococcus variants in the laboratory at St. Mary's Hospital variants in the laboratory at St. Mary's Hospital in London. He observed that a mold contaminating one of his in London. He observed that a mold contaminating one of his cultures caused the bacteria in its vicinity to undergo lysis. cultures caused the bacteria in its vicinity to undergo lysis. Broth in which the fungus was grown was markedly inhibitory Broth in which the fungus was grown was markedly inhibitory for many microorganisms. Because the mold belonged to the for many microorganisms. Because the mold belonged to the genus genus Penicillium,Penicillium, Fleming named the antibacterial substance Fleming named the antibacterial substance penicillin (meaning brave).penicillin (meaning brave). In 1941 Penicillin was developed as systemic therapeutic agent In 1941 Penicillin was developed as systemic therapeutic agent & tested on an old terminally ill lady having cancer& tested on an old terminally ill lady having cancer1944 on war soldier having multiple wounds 1944 on war soldier having multiple wounds

PENICILLINS - PENICILLINS - ChemistryChemistry

The basic structure of the penicillins The basic structure of the penicillins consists of a thiazolidine ring (A) consists of a thiazolidine ring (A) connected to a connected to a ββ -lactam ring (B) to -lactam ring (B) to which is attached a side chain (R) -- which is attached a side chain (R) -- 6 6 Aminopenicillanic acid Aminopenicillanic acid The penicillin nucleus itself is the The penicillin nucleus itself is the chief structural requirement for chief structural requirement for biological activity; metabolic biological activity; metabolic transformation or chemical alteration transformation or chemical alteration of this portion of the molecule causes of this portion of the molecule causes loss of all significant antibacterial loss of all significant antibacterial activityactivityHydrolysis of the Hydrolysis of the ββ -lactam ring by -lactam ring by bacterial bacterial ββ -lactamases yields -lactamases yields penicilloic acid, which lacks penicilloic acid, which lacks antibacterial activity.antibacterial activity.

PENICILLINS – PENICILLINS – Chemistry…Chemistry…

The side chain determines many of The side chain determines many of the antibacterial and the antibacterial and pharmacological characteristics of pharmacological characteristics of a particular type of penicillina particular type of penicillinSeveral natural penicillins can be Several natural penicillins can be produced depending on the produced depending on the chemical composition of the chemical composition of the fermentation medium used to fermentation medium used to culture culture PenicilliumPenicilliumPenicillin G (benzylpenicillin) has Penicillin G (benzylpenicillin) has the greatest antimicrobial activity the greatest antimicrobial activity of these and is the only natural of these and is the only natural penicillin used clinically. For penicillin used clinically. For penicillin G, the side chain is a penicillin G, the side chain is a phenyl-methyl substituent phenyl-methyl substituent

Chemistry:Chemistry:

Classification of PenicillinsClassification of Penicillins

1- Natural Penicillin And Its Congener1- Natural Penicillin And Its Congener Penicillin G/ BenzylpenicillinPenicillin G/ Benzylpenicillin

Penicillin V /Phenoxymethylpenicillin.Penicillin V /Phenoxymethylpenicillin.

2- Semi-synthetic Penicillins2- Semi-synthetic Penicillinsa. a. lactamase Resistant Penicillins lactamase Resistant Penicillins

i. i. MethicillinMethicillin ii. Nafcillinii. Nafcillin iii. iii. Isoxazolyl PenicillinsIsoxazolyl Penicillins Oxacillin, CloxacillinOxacillin, Cloxacillin Di-cloxacillin, Flucloxacillin.Di-cloxacillin, Flucloxacillin.

b. Extended Spectrumb. Extended Spectrum

i. Aminopenicillinsi. Aminopenicillins Amoxicillin, Ampicillin Amoxicillin, Ampicillin Ampicillin prodrugs:Ampicillin prodrugs:

• Piv-ampicillinPiv-ampicillin• Bac-ampicillinBac-ampicillin• Tal-ampicillinTal-ampicillin

Classification of Penicillins…Classification of Penicillins…

ii. Antipseudomonal Penicillinsii. Antipseudomonal Penicillins

a. Carboxypenicillinsa. Carboxypenicillins

Carbenicillin , Ticarcillin Carbenicillin , Ticarcillin

b.b. UreidopenicillinsUreidopenicillins

Azlocillin , Mezlocillin , PiperacillinAzlocillin , Mezlocillin , Piperacillin

Classification of Penicillins…Classification of Penicillins…

Combinations of Combinations of Penicillins with Penicillins with - Lactamase - Lactamase InhibitorsInhibitorsAmoxicillin / Clavulanate ( Augmentin)Amoxicillin / Clavulanate ( Augmentin)

Ampicillin / Sulbactum Ampicillin / Sulbactum

Piperacillin / TazobactumPiperacillin / Tazobactum

Ticarcillin / ClavulanateTicarcillin / Clavulanate

Penicillin Units & FormulationsPenicillin Units & Formulations

Activity ofActivity of Penicillin G originally expressed in UnitsPenicillin G originally expressed in Units

One unit =0.6 One unit =0.6 μμg; One million units =0.6 g g; One million units =0.6 g

Crystalline sodium Penicillins contains approx.-1600units / mgCrystalline sodium Penicillins contains approx.-1600units / mg

Semi synthetic penicillin are prescribed by weightSemi synthetic penicillin are prescribed by weight

Penicillins are dispensed as sodium / Potassium salts. Penicillins are dispensed as sodium / Potassium salts. • Potassium Penicillin G contains KPotassium Penicillin G contains K++ 2.8 mEq/g 2.8 mEq/g• Nafcillin contains KNafcillin contains K++ 2.8 mEq/g 2.8 mEq/g

Stability:Stability:Dry crystalline form stable at 4Dry crystalline form stable at 4ooC for years. C for years.

Solutions lose activity in 24 hrs at 20Solutions lose activity in 24 hrs at 20ooC --- must be prepared freshC --- must be prepared fresh

MOA of PenicillinsMOA of Penicillins

BactericidalBactericidal

Bacterial cell wall synthesis InhibitorsBacterial cell wall synthesis Inhibitors

Only act when bacteria are rapidly growing & Only act when bacteria are rapidly growing & synthesizing cell wall.synthesizing cell wall.

Have time dependent (Concentration independent Have time dependent (Concentration independent killing)killing)

Entry in to G+ve bacteria through bacterial cell wall & Entry in to G+ve bacteria through bacterial cell wall & G –ve bacteria through porins in the outer cell wall, G –ve bacteria through porins in the outer cell wall, which is absent in G+ve bacteria.which is absent in G+ve bacteria.

MOA of Penicillins…MOA of Penicillins…

Penicillins act by following stepsPenicillins act by following steps1. Binding to their receptors----specific enzymes, PBPs 1. Binding to their receptors----specific enzymes, PBPs 2. Inhibition of transpeptidation reaction / cross linking 2. Inhibition of transpeptidation reaction / cross linking

of linear peptidoglycans chains of the cell wall.of linear peptidoglycans chains of the cell wall. So synthesis of bacterial cell wall is inhibited. So synthesis of bacterial cell wall is inhibited. 3. Activation of autolysins, disruption of cell 3. Activation of autolysins, disruption of cell

morphogenesis & Cell death.morphogenesis & Cell death.

1.Binding to receptors1.Binding to receptors Penicillin Binding Proteins (PBPs) are transpeptidase enzymes Penicillin Binding Proteins (PBPs) are transpeptidase enzymes

in bacterial cytoplasmic membrane. in bacterial cytoplasmic membrane. They catalyze the final step in the synthesis of peptidoglycan; They catalyze the final step in the synthesis of peptidoglycan;

important part of bacterial cell wallimportant part of bacterial cell wall

2. Inhibition of transpeptidation reaction2. Inhibition of transpeptidation reactionBacterial cell wall consists of outer membrane & Bacterial cell wall consists of outer membrane & Peptidoglycan Peptidoglycan Peptidoglycan is unique to bacteria cell wall & is much Peptidoglycan is unique to bacteria cell wall & is much thicker in G+ve than in G-ve bacteria.thicker in G+ve than in G-ve bacteria.


It consists of polysaccharides (N-acetylglucosamine & N-It consists of polysaccharides (N-acetylglucosamine & N-acetylmuramic acid) & polypeptides. acetylmuramic acid) & polypeptides. A five amino acid peptide is linked to the N-acetylmuramic acid A five amino acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alaninesugar. This peptide terminates in D-alanyl-D-alaninePBPs remove the terminal Alanine in the process of cross linking PBPs remove the terminal Alanine in the process of cross linking with a nearby peptide in transpeptidation reaction. with a nearby peptide in transpeptidation reaction. ββ-lactam drugs are structural analogs of natural substrate. -lactam drugs are structural analogs of natural substrate. D-alanyl-D-alanyl-D-alanine.D-alanine.Penicillins bind to active site of PBPs, this inhibits transpeptidation Penicillins bind to active site of PBPs, this inhibits transpeptidation reaction -- cross linking reaction -- cross linking So the synthesis of Peptidoglycans / cell wall is inhibitedSo the synthesis of Peptidoglycans / cell wall is inhibited


33. Cell death. Cell death

Disinhibition /Activation of autolysins Disinhibition /Activation of autolysins May bacteria produce autolysins (degradative enzymes) that May bacteria produce autolysins (degradative enzymes) that

participate in the normal remodeling of the cell wall. Otherwise participate in the normal remodeling of the cell wall. Otherwise they are inhibited.they are inhibited.

In the presence of Penicillins they are disinhibited & degradative In the presence of Penicillins they are disinhibited & degradative action occurs in the absence of cell wall synthesis.action occurs in the absence of cell wall synthesis.

--- --- Destruction of cell ---- lysisDestruction of cell ---- lysis


Mech. Of bacterial resistance to penicillinsMech. Of bacterial resistance to penicillins

Enzymatic hydrolysis of drug ---- by beta lactamasesEnzymatic hydrolysis of drug ---- by beta lactamases– Many hundred types.Many hundred types.– Those produced by Staph aureus , Hemophilus , & E coli have Those produced by Staph aureus , Hemophilus , & E coli have

narrow substrate specificity narrow substrate specificity – Those produced by Pseudomonas & Enterobacter can hydrolyze Those produced by Pseudomonas & Enterobacter can hydrolyze

Penicillins & CephalosporinsPenicillins & Cephalosporins

Altered target PBPsAltered target PBPs– basis of Methicillin resistance in Staph (MRSA) & Penicillin basis of Methicillin resistance in Staph (MRSA) & Penicillin

resistance in Pneumococci & enterococciresistance in Pneumococci & enterococci

Mech. Of bacterial resistance to penicillinsMech. Of bacterial resistance to penicillins

Impaired penetration of drug to target PBPsImpaired penetration of drug to target PBPs– Only in G-ve bacteria due to resistant outer cell membrane– Only in G-ve bacteria due to resistant outer cell membrane–

porins may be absent or decreasedporins may be absent or decreased

– This is more important if bacteria is also beta lactamase This is more important if bacteria is also beta lactamase producing.producing.

Active efflux pumpActive efflux pump– May be producedMay be produced in G-ve bacteria in G-ve bacteria

Benzyl penicillinBenzyl penicillin ( (Penicillin G)Penicillin G)

Benzyl penicillinBenzyl penicillin ( (Penicillin G)Penicillin G)

Natural penicillinNatural penicillin

Acid labile – not effective orallyAcid labile – not effective orally

SourceSource

Obtained from fermentation of mold Penicillium chrysogenum Obtained from fermentation of mold Penicillium chrysogenum in huge tanks.in huge tanks.

Structure: Next slideStructure: Next slide

MOA --- already discussedMOA --- already discussed

Chemistry:Chemistry:

Ph. K - Benzyl Penicillin (Penicillin G)Ph. K - Benzyl Penicillin (Penicillin G)

Route of AdministrationRoute of Administrationacid labile, so given I/V.acid labile, so given I/V.

• 4 – 24 million units/d I/V 4-6 in divided doses.4 – 24 million units/d I/V 4-6 in divided doses.• I/V infusion may be given—for large doses.I/V infusion may be given—for large doses.• Never intrathecally--- convulsionsNever intrathecally--- convulsions• Topical application avoided –risk of allergyTopical application avoided –risk of allergy• I/M InjectionI/M Injection only Repository preparations only Repository preparations

Procaine Penicillin – 1-2 inj /dProcaine Penicillin – 1-2 inj /dBenzathine Penicillin 1.2 million units every 3-4 Benzathine Penicillin 1.2 million units every 3-4 wks-for prophylaxiswks-for prophylaxis

2.4 million units once a week for 1-3 wks for treatment 2.4 million units once a week for 1-3 wks for treatment of syphilis.of syphilis.

Ph. K - Benzyl Penicillin (Penicillin G)…Ph. K - Benzyl Penicillin (Penicillin G)…

Distribution:Distribution:

Distributed in body fluids but poor conc in the cells as it is Distributed in body fluids but poor conc in the cells as it is polar.polar.

Penetration into brain, eye & prostate poor.Penetration into brain, eye & prostate poor.

Crosses BBB only if meninges are inflamed.Crosses BBB only if meninges are inflamed.

Crosses placental barrier Crosses placental barrier

Also excreted in breast milk & sputum.Also excreted in breast milk & sputum.

PPB: lowPPB: low


MetabolismMetabolism

Not metabolized significantly in host, but in impaired Not metabolized significantly in host, but in impaired renal function some metabolism of Penicillin G has been renal function some metabolism of Penicillin G has been shown to occur.shown to occur.

(Bacteria may hydrolyze 6APA to Penicilloic acid (Bacteria may hydrolyze 6APA to Penicilloic acid which has no bacterial activity but is antigenic)which has no bacterial activity but is antigenic)


Excretion:Excretion: Rapid excretion by kidneys—10% GFRapid excretion by kidneys—10% GF

90% --Active tubular secretion via organic acid transporter, 90% --Active tubular secretion via organic acid transporter, competitively inhibited by Probenecidcompetitively inhibited by Probenecid

So co-admintration of 0.5g Probenecid can raise the blood So co-admintration of 0.5g Probenecid can raise the blood levels& levels& ↓the frequency of injections.↓the frequency of injections.

Elimination less effective in neonates.Elimination less effective in neonates.

Plasma half life (tPlasma half life (t1/21/2))

Short—30 minutes prolonged in renal failure—10 hrs.Short—30 minutes prolonged in renal failure—10 hrs.

Dosage adjustment according to creatinine clearance.Dosage adjustment according to creatinine clearance.

Active against following Penicillin susceptible organismsActive against following Penicillin susceptible organisms

Streptococci: pyogenes & viridansStreptococci: pyogenes & viridansMeningococci Meningococci PneumococciPneumococciGonococci (Non – Gonococci (Non – lactamase producing) lactamase producing)Staphylococci (Non – Staphylococci (Non – lactamase producing) lactamase producing)Treponema Pallidum & other spirochetesTreponema Pallidum & other spirochetesClostridium perfringesClostridium perfringesActinomyces Actinomyces Non Non ββ-lactamase producing G-ve anaerobic organisms. -lactamase producing G-ve anaerobic organisms.

Spectrum Of Activity of Penicillin GSpectrum Of Activity of Penicillin G

USES OF BENZYLPENICILLINUSES OF BENZYLPENICILLIN

DoseDose 4 – 24 million units/d I/V 4-6 divided doses. 4 – 24 million units/d I/V 4-6 divided doses.I/V infusion may be given—for large dosesI/V infusion may be given—for large doses

1.1. -Haemolytic Streptococcal (Strept. pyogenes) infections -Haemolytic Streptococcal (Strept. pyogenes) infections such as:such as:

• Acute Tonsillitis & PharyngitisAcute Tonsillitis & Pharyngitis• Scarlet fever Scarlet fever • PneumoniaPneumonia• Arthritis Arthritis • Meningitis Meningitis • EndocarditisEndocarditis• Strepcoccal toxic shock & Necrotizing Strepcoccal toxic shock & Necrotizing Fascitis Fascitis with with

clindamycin. clindamycin.

2.2. Strep. viridans Endocarditis (Strep. viridans Endocarditis (The The viridansviridans streptococci are the streptococci are the most common cause of infectious endocarditis )most common cause of infectious endocarditis )

3.3. Pneumococcal Pneumonia , Pneumococcal Meningitis Pneumococcal Pneumonia , Pneumococcal Meningitis 4.4. Meningococcal meningitis (Massive doses).Meningococcal meningitis (Massive doses).5.5. Staphylococcal Infections (non Staphylococcal Infections (non -lactamase producing strains -lactamase producing strains

only).only).6. Enterococcal endocarditis with aminoglycosides6. Enterococcal endocarditis with aminoglycosides7. Syphilis: Single inj of Benzathine Penicillin G I/M 2.4 million 7. Syphilis: Single inj of Benzathine Penicillin G I/M 2.4 million

units once a week for 1-3 wks. No antibiotic resistance has been units once a week for 1-3 wks. No antibiotic resistance has been reported.reported.

8.8. ActinomycosisActinomycosis9.9. Clostridial infections (gas gangrene)Clostridial infections (gas gangrene)

USES OF BENZYLPENICILLIN…USES OF BENZYLPENICILLIN…

Prophylactic Uses of Penicillin GProphylactic Uses of Penicillin G

ProphylaxisProphylaxisBenzathine Penicillin I/M 1.2 million units once /3-4 wksBenzathine Penicillin I/M 1.2 million units once /3-4 wks

Streptococcal infectionsStreptococcal infections

Recurrences of rheumatic feverRecurrences of rheumatic fever

Surgical procedures in Pt. with Valvular heart disease.Surgical procedures in Pt. with Valvular heart disease.

PHENOXY METHYL PENICILLIN PHENOXY METHYL PENICILLIN (Penicillin V)(Penicillin V)

Differences from Penicillin GDifferences from Penicillin G1.1. Gastric acid resistant--- Gastric acid resistant--- Orally effective, but poor bioavailability.Orally effective, but poor bioavailability.2.2. Narrow antibacterial spectrum.Narrow antibacterial spectrum.3.3. Less potent Less potent

Therapeutic Uses Therapeutic Uses Only for Only for mild streptococcal & pneumococcal infectionsmild streptococcal & pneumococcal infections Pharyngitis , Sinusitis , Otitis media.Pharyngitis , Sinusitis , Otitis media.

SEMISYNTHETIC PENCILLINSSEMISYNTHETIC PENCILLINS

aa. . lactamase Resistant Penicillins lactamase Resistant Penicillins

i. Nafcillin i. Nafcillin

ii. ii. Isoxazolyl PenicillinsIsoxazolyl Penicillins

Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin

iii. Methicillin is not used; due to renal toxicity - iii. Methicillin is not used; due to renal toxicity - interstitial nephritisinterstitial nephritis

Ph.K - Ph.K - lactamase Resistant Penicillin lactamase Resistant Penicillin

All are acid stable; Effective orally except All are acid stable; Effective orally except NafcillinNafcillin (erratic abs) (erratic abs)

Abs: Abs: Well absorbed, abs is delayed by food so given 1-2 hrs Well absorbed, abs is delayed by food so given 1-2 hrs before of after meals. before of after meals. Flucloxacillin– best absorbedFlucloxacillin– best absorbed

Elimination:Elimination:

Oxacillin , Cloxacillin , Dicloxacillin , Flucloxacillin. Oxacillin , Cloxacillin , Dicloxacillin , Flucloxacillin.

Eliminated both by kidney & biliary excretionEliminated both by kidney & biliary excretion

Nafcillin - Nafcillin - biliary excretionbiliary excretion & highly PPB & highly PPB

THERAPEUTIC USES THERAPEUTIC USES

lactamase Resistant Penicillins lactamase Resistant Penicillins

Infections by beta lactamase (Penicillinase) Infections by beta lactamase (Penicillinase) producing staphylococcus aureus (except methicillin producing staphylococcus aureus (except methicillin resistant Staph-aureus ---- MRSA)resistant Staph-aureus ---- MRSA)

For mild InfectionFor mild Infection

Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin orally.Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin orally.

For severe InfectionFor severe Infection

Oxacillin or Nafcillin by intermittent Oxacillin or Nafcillin by intermittent I/V infusion. .I/V infusion. .

Extended spectrum PenicillinsExtended spectrum Penicillins

Excreted more slowly than Penicillin G.Excreted more slowly than Penicillin G.

Enhanced ability to penetrate outer membrane of Gram –ve Enhanced ability to penetrate outer membrane of Gram –ve bacteria -- So greater activity than Penicillin G against Gram –bacteria -- So greater activity than Penicillin G against Gram –ve bacteria.ve bacteria.

They are inactivated by most Beta lactamases. They are inactivated by most Beta lactamases.

May be combined with Beta lactamase inhibitorsMay be combined with Beta lactamase inhibitors

AMINOPENCILLINSAMINOPENCILLINSAMOXICILLIN, AMPICILLIN & PRODRUGSAMOXICILLIN, AMPICILLIN & PRODRUGS

PharmacokineticsPharmacokineticsAll are acid stable, effective orally. Can be used I/M or I/V All are acid stable, effective orally. Can be used I/M or I/V Abs:Abs: Well absorbed, delayed by food (except amoxicillin) so Well absorbed, delayed by food (except amoxicillin) so given 1-2 hrs before of after meals.given 1-2 hrs before of after meals.Amoxicillin better abs than Ampicillin, so Amoxicillin 250-500 Amoxicillin better abs than Ampicillin, so Amoxicillin 250-500 mg 8 hrly = Ampicillin 250-500 mg given 6 hrly mg 8 hrly = Ampicillin 250-500 mg given 6 hrly As Ampicillin is less completely absorbed so is effective in As Ampicillin is less completely absorbed so is effective in Shigella dysentery & can disturb the normal flora also.Shigella dysentery & can disturb the normal flora also.Elimination:Elimination: Renal Renal—10% GF &90% --Active tubular secretion —10% GF &90% --Active tubular secretion Ampicillin also excreted in feces.Ampicillin also excreted in feces.

Antibacterial spectrum - AminopenicillinsAntibacterial spectrum - Aminopenicillins

Have antibacterial spectrum of penicillin G, but more active against G-ve Have antibacterial spectrum of penicillin G, but more active against G-ve bacilli ---extended spectrumbacilli ---extended spectrum– Resistance due to plasmid –mediated penicillinases is a major Resistance due to plasmid –mediated penicillinases is a major

problemproblem– Combined with a beta lactamase inhibitor -- Clavulanic acid / Combined with a beta lactamase inhibitor -- Clavulanic acid /

sulbactumsulbactumPneumococci (resistant to Pen. G)Pneumococci (resistant to Pen. G)Listeria monocytogenese -- Ampicillin is the DOCListeria monocytogenese -- Ampicillin is the DOCH-influanzae (Non- H-influanzae (Non- lactamase producing--- lactamase producing---resistance developing)resistance developing)Salmonella Salmonella ShigellaShigellaE-coli E-coli Gonococci Gonococci Helicobacter pylori Helicobacter pylori

Therapeutic Uses - AminopenicillinsTherapeutic Uses - Aminopenicillins

Respiratory Tract InfectionsRespiratory Tract InfectionsSpecially Streptococcal , Pneumococcal & H- Influenzae infections:Specially Streptococcal , Pneumococcal & H- Influenzae infections:

• SinusitisSinusitis• Otitis media in children.Otitis media in children.• Bronchitis , Pneumonia .Bronchitis , Pneumonia .

Bacterial MeningitisBacterial Meningitis Specially in Children by S. Pneomonias or N. MeningitidisSpecially in Children by S. Pneomonias or N. Meningitidis

In immunocompromised persons by Listeria. monocytogenes (Ampicillin) In immunocompromised persons by Listeria. monocytogenes (Ampicillin)

Uncomplicated UTI by E. Coli (Ampicillin)Uncomplicated UTI by E. Coli (Ampicillin)(Fluoroquinolones / co-trimoxazole are preferred because of resistance)(Fluoroquinolones / co-trimoxazole are preferred because of resistance)

GonorrheaGonorrhea (Amoxicillin + clavulanate) (Amoxicillin + clavulanate)

Therapeutic Uses – Aminopenicillins…Therapeutic Uses – Aminopenicillins…

Bacillary dysentery by Shigella ---AmpicillinBacillary dysentery by Shigella ---Ampicillin

(but Should not be used for Salmonella diarrhea as it may prolong the carrier (but Should not be used for Salmonella diarrhea as it may prolong the carrier state)state)

Typhoid feverTyphoid fever (Amoxicillin). (Amoxicillin).

Prophylaxis of Subacute bacterial endocarditisProphylaxis of Subacute bacterial endocarditis in abnormal valves by dentists in abnormal valves by dentists before extensive oral surgery..before extensive oral surgery..

E. Coli SepticaemiaE. Coli Septicaemia with gentamicin. with gentamicin.

Eradication of H-pyloriEradication of H-pylori as a part of regimen in peptic ulcer (Amoxicillin). as a part of regimen in peptic ulcer (Amoxicillin).

Antipseudomonal PenicillinsAntipseudomonal Penicillins

CarboxypenicillinsCarboxypenicillins: Carbenicillin, Ticarcillin: Carbenicillin, Ticarcillin

Ureidopenicillins: Ureidopenicillins: Azlocillin, Mezlocillin, PiperacillinAzlocillin, Mezlocillin, Piperacillin

– As they are susceptible to penicillinases --- combined with As they are susceptible to penicillinases --- combined with Beta lactamase inhibitorsBeta lactamase inhibitors

– Synergistic Synergistic with an Aminoglycosideswith an Aminoglycosides

CarboxypenicillinsCarboxypenicillins

CarbenicillinCarbenicillin –First carboxy penicillin is obsolete –First carboxy penicillin is obsolete

Now Now Carbenicillin Indanyl sodiumCarbenicillin Indanyl sodium is used orally - is used orally - congener is the indanyl ester of carbenicillin congener is the indanyl ester of carbenicillin

TicarcillinTicarcillin– I/V– I/V

Carboxypenicillins….Carboxypenicillins….

Antibacterial spectrumAntibacterial spectrum– Pseudomonas aeruginosa & ProteusPseudomonas aeruginosa & Proteus

Therapeutic UsesTherapeutic Uses – UTI UTI caused by pseudomonas aeruginosa / Proteuscaused by pseudomonas aeruginosa / Proteus

– In other pseudomonal infections with AminoglycosidesIn other pseudomonal infections with Aminoglycosides

UreidopenicillinsUreidopenicillins

Antibacterial spectrumAntibacterial spectrum– Klebsiella pneumoniae , Proteus & Pseudomonas aeruginosaKlebsiella pneumoniae , Proteus & Pseudomonas aeruginosa

Therapeutic UsesTherapeutic Uses– Serious infections by sensitive G -ve BacteriaSerious infections by sensitive G -ve Bacteria

UTI UTI Infections after burns Infections after burns BacteremiaBacteremiaIn neutropenic & immunocompromised PatientsIn neutropenic & immunocompromised PatientsMay be combined with Aminoglycosides May be combined with Aminoglycosides

Adverse Reactions - PenicillinsAdverse Reactions - Penicillins

Penicillins are remarkably safePenicillins are remarkably safe

Mainly Hypersensitivity reactionsMainly Hypersensitivity reactions

Adverse Reactions - PenicillinsAdverse Reactions - Penicillins

Hypersensitivity / Allergic reactionsHypersensitivity / Allergic reactionsManifestations include maculopapular rash, urticarial rash, Manifestations include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxisdermatitis, Stevens-Johnson syndrome, and anaphylaxis

– The most important A/E. ---5%The most important A/E. ---5%– Major antigenic determinant: Metabolite Penicilloic acid - Major antigenic determinant: Metabolite Penicilloic acid - act act

as haptens after covalent reaction with proteins --as haptens after covalent reaction with proteins --causes causes immunological reaction.immunological reaction.

– Cross allergenic with Beta lactamsCross allergenic with Beta lactams– Desensitization may be done Desensitization may be done

Adverse Reactions – Penicillins…Adverse Reactions – Penicillins…

A: Acute anaphylaxis /Anaphylactic shock. A: Acute anaphylaxis /Anaphylactic shock. 0.5% ,may be fatal.0.5% ,may be fatal.

B. Skin rashes of various types.B. Skin rashes of various types.

C. Serum sickness like syndrome C. Serum sickness like syndrome —7-10 d after—7-10 d after exposure.exposure.

D. Allergic Renal disturbances D. Allergic Renal disturbances (Interstitial nephiritis specially with methicillin..(Interstitial nephiritis specially with methicillin..

E. Allergic Blood disturbances. E. Allergic Blood disturbances. Eosinophilia hemolytic anemiaEosinophilia hemolytic anemia

F. Vasculitis.F. Vasculitis.


Other A/E of Pen. G:Other A/E of Pen. G: Pain after IM injection.Pain after IM injection. ThrombophlebitisThrombophlebitis after I/V injection. after I/V injection. SeizuresSeizures. Large doses in renal failure. Large doses in renal failure Arachnoiditis Arachnoiditis encephalopathy - after Intrathecal inj.encephalopathy - after Intrathecal inj. HyperkalemiaHyperkalemia in renal dysfunction with large doses of Pen. G in renal dysfunction with large doses of Pen. G

potassiumpotassium Dizziness, tinnitus, headache, hallucination, seizures --Dizziness, tinnitus, headache, hallucination, seizures -- Pen. G Pen. G

procaine . procaine .


Cation Toxicity:Cation Toxicity: Penicillins are generally given as Sodium or Patassium saltsPenicillins are generally given as Sodium or Patassium salts So when used in large doses-- Sodium or Potassium toxicity So when used in large doses-- Sodium or Potassium toxicity

may occur.may occur. HyperkalemiaHyperkalemia in renal dysfunction with large doses of Pen. G in renal dysfunction with large doses of Pen. G

potassium.potassium. HypokalemiaHypokalemia with sodium excess. with sodium excess. It can be avoided by using the most potent drug – in lower dosesIt can be avoided by using the most potent drug – in lower doses


Jerisch Herxhimier Reaction:Jerisch Herxhimier Reaction:

Symptoms:Symptoms: Several hours after the first inj in syphilis patient Several hours after the first inj in syphilis patient

--chills, fever, headache, myalgias, arthopathy & prominence of --chills, fever, headache, myalgias, arthopathy & prominence of cutaneous lesions.cutaneous lesions.

Remedy: Discontinue penicillinRemedy: Discontinue penicillin

Give Inj HydrocortisoneGive Inj Hydrocortisone

Cause: DueCause: Due to killing of a large number of spirochetes, libration to killing of a large number of spirochetes, libration of toxinsof toxins


NafcillinNafcillin --- neutropenia --- neutropenia

OxacillinOxacillin --- hepatitis --- hepatitis

MethicillinMethicillin --- interstitial nephritis --- interstitial nephritis

AmpicillinAmpicillin

GIT upset , nausea, vomiting, and diarrhea.GIT upset , nausea, vomiting, and diarrhea.

Super infection i.e. Pseudomembranous colitis , Vaginal Super infection i.e. Pseudomembranous colitis , Vaginal candidiasis.candidiasis.

AmpicillinAmpicillin and and AmoxicillinAmoxicillin can cause skin rashes that are not can cause skin rashes that are not allergic in nature.allergic in nature.

Beta lactamase inhibitors (Clavulanic acid, Beta lactamase inhibitors (Clavulanic acid, Sulbactam, & Tazobactam)Sulbactam, & Tazobactam)

Beta lactamase inhibitors (Clavulanic acid, Sulbactam, & Tazobactam)Beta lactamase inhibitors (Clavulanic acid, Sulbactam, & Tazobactam)

Resemble Resemble ββ-lactam molecule.-lactam molecule.

Almost Almost NO antibacterial action.NO antibacterial action.

Potent inhibitors of many but not all Potent inhibitors of many but not all ββ-lactamases.-lactamases.

Protect hydrolyzable penicillins from inactivationProtect hydrolyzable penicillins from inactivation

Most active against Most active against Ambler class A Ambler class A ββ-lactamases.-lactamases.

produced by staphylococci, H. influenzae, N. gonorrhoeae, salmonella, produced by staphylococci, H. influenzae, N. gonorrhoeae, salmonella, shigella, E coli &shigella, E coli &

K Pneumoniae.K Pneumoniae.

Not good inhibitors of class Not good inhibitors of class C C ββ-lactamases-lactamases, which typically are , which typically are chromosomally encoded and inducible. Produced by chromosomally encoded and inducible. Produced by enterobacter, citrobacter, enterobacter, citrobacter, serratia, and pseudomonasserratia, and pseudomonas..

They do inhibit chromosomal They do inhibit chromosomal ββ-lactamases of legionella, bacteroides, and -lactamases of legionella, bacteroides, and branhamellabranhamella..

Available only in fixed combinations with specific penicillins.Available only in fixed combinations with specific penicillins.

Antibacterial spectrumAntibacterial spectrum --- determined by the penicillin, not the --- determined by the penicillin, not the ββ-lactamase -lactamase inhibitors.inhibitors.

Extend the spectrum of a penicillin.Extend the spectrum of a penicillin.Combinations of Combinations of Penicillins with Penicillins with - Lactamase Inhibitors- Lactamase Inhibitors

Amoxicillin / Clavulanate ( Augmentin)Amoxicillin / Clavulanate ( Augmentin)

Ampicillin / Sulbactum Ampicillin / Sulbactum

Piperacillin / TazobactumPiperacillin / Tazobactum

Ticarcillin / ClavulanateTicarcillin / Clavulanate

Th. IndicationsTh. Indications for penicillin - for penicillin - ββ-lactamase inhibitor combinations are:-lactamase inhibitor combinations are:

– Empirical therapy for infections caused by a wide range of Empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised & potential pathogens in both immunocompromised & immunocompetent patients.immunocompetent patients.

– Treatment of mixed aerobic & anaerobic infections i.e. intra-Treatment of mixed aerobic & anaerobic infections i.e. intra-abdominal infections.abdominal infections.

– Dosage adjustment according to the penicillin.Dosage adjustment according to the penicillin.

Monobactams:Monobactams: Drugs withDrugs with ββ-lactam monocyclic ring -lactam monocyclic ring

Aztreonam:Aztreonam:

MOA: MOA: inhibition of bacterial cell wall synthesis.inhibition of bacterial cell wall synthesis.

Binds to PBPBinds to PBP3 3 & synergistic with aminoglycosides.& synergistic with aminoglycosides.

Resistant toResistant to ββ-lactamases -lactamases

Active only Active only against G-ve rods including Pseudomonas & against G-ve rods including Pseudomonas & Serretia.Serretia.

No cross allergenicity with penicillin.No cross allergenicity with penicillin.

So penicillin allergic patients tolerate Aztreonam very well. So penicillin allergic patients tolerate Aztreonam very well.

Carbepenems:Carbepenems:

Ertapenem , Imipenem/cilasatin , meropenem:Ertapenem , Imipenem/cilasatin , meropenem:

ββ-lactam drugs-lactam drugs

Resistant to mostResistant to mostββ-lactamases except -lactamases except Metallo Metallo ββ-lactamases -lactamases

Active against G-ve rods including Pseudomonas,Active against G-ve rods including Pseudomonas,

G+ve organisms. & anaerobes .G+ve organisms. & anaerobes .

Cross allergenic with PenicillinsCross allergenic with Penicillins

Th. uses:Th. uses:

Enterobactor infection.--- DOCEnterobactor infection.--- DOC

Infections by Penicillin resistant pneumococci. Infections by Penicillin resistant pneumococci.

Pseudomonal infection with Aminoglycoside.Pseudomonal infection with Aminoglycoside.

A/E:A/E: NVD , skin rashes ,Reaction at infusion site, Seizures in renal failure. NVD , skin rashes ,Reaction at infusion site, Seizures in renal failure. (imipenum)(imipenum)

Cross allergenic with PenicillinsCross allergenic with Penicillins

Non-Non-ββ-lactam Inhibitors of bacterial cell wall synthesis-lactam Inhibitors of bacterial cell wall synthesisVancomycin:Vancomycin: Source:Source: Glycopeptide Antibiotic --- Streptococcus orientalis. Glycopeptide Antibiotic --- Streptococcus orientalis.Antibacterial spectrum:Antibacterial spectrum: Narrow ,against resistant micro-org. Narrow ,against resistant micro-org.

G +ve bacteria, specially Staphylococcus, even MRSAG +ve bacteria, specially Staphylococcus, even MRSAClostridium difficile. Clostridium difficile.

Ph.K:Ph.K:

Poorly absorbed form intestine.Poorly absorbed form intestine.

Orally effective only for enterocolitis. Orally effective only for enterocolitis.

For systemic infections--by I/V infusion.For systemic infections--by I/V infusion.

90% excreted by GF90% excreted by GF

Drug is not removed by hemodialysis Drug is not removed by hemodialysis

MOA: MOA: Bactericidal Bactericidal

Binds to the Binds to the D-Ala-D-AlaD-Ala-D-Ala terminal of the nascent terminal of the nascent peptidoglycan pentapeptide side chain peptidoglycan pentapeptide side chain

Inhibits Inhibits transglycosylation. transglycosylation.

So prevents elongation of the peptidoglycan chain & So prevents elongation of the peptidoglycan chain & interferes with cross linking. interferes with cross linking.

MOR:MOR:Alteration of D-Ala-D-Ala binding site & loss of Alteration of D-Ala-D-Ala binding site & loss of affinity & activity. affinity & activity.

Therapeutic uses: Therapeutic uses: Narrow spectrum ,Narrow spectrum , Serious infection by drug resistant G +ve Serious infection by drug resistant G +ve

organisms.organisms.Sepsis or endocarditis by MRSA / severe penicillin allergy. Sepsis or endocarditis by MRSA / severe penicillin allergy. I/V I/V Pneumococcal Meningitis with 3Pneumococcal Meningitis with 3rdrd gen .Cephalosporins gen .Cephalosporins (Cefotaxine, Ceftriaxone) or Rifampin. (Cefotaxine, Ceftriaxone) or Rifampin. I/V I/V Antibiotic induced Enterocolitis by Clostridium difficile. Antibiotic induced Enterocolitis by Clostridium difficile. Orally Orally for refractory cases.for refractory cases.

First DOC -- MetronidazoleFirst DOC -- Metronidazole

A/E:A/E:

Rapid I/V infusion , “Rapid I/V infusion , “Redman” or “Red neck” Redman” or “Red neck” syndrome due to histamine release .syndrome due to histamine release .

PhlebitisPhlebitis

Chills & fever ,Chills & fever ,

Ototoxicity & Nephrotoxicity. (rare)Ototoxicity & Nephrotoxicity. (rare)

Teicoplanin:Teicoplanin:

Similar to Vancomycin. Can be given I/M , I/V.Similar to Vancomycin. Can be given I/M , I/V.

Daptomycin:Daptomycin:Source:Source: Streptomyces roseoporus Streptomyces roseoporus

Cleared renallyCleared renally

Spectrum of activity similar to vancomycin, even effective against Spectrum of activity similar to vancomycin, even effective against vancomycin resistant strains of enteroccoci & S. aureus.vancomycin resistant strains of enteroccoci & S. aureus.

MOA:MOA: Not clear. Not clear.

Binds to & depolarizes the cell membrane, potassium efflux & Binds to & depolarizes the cell membrane, potassium efflux & cell deathcell death

Th. Uses:Th. Uses: Alternative to vancomycin. Alternative to vancomycin.

A/E:A/E: Myopathy. Myopathy.

Fosfomycin: Fosfomycin:

Analog of Phosphoenolpyruvic acid.Analog of Phosphoenolpyruvic acid.

MOA: MOA: Inhibits early stage of bacterial cell wall Inhibits early stage of bacterial cell wall synthesissynthesis

Inhibits cytoplasmic enolpyruvate transferase.Inhibits cytoplasmic enolpyruvate transferase.

Prevents formation of N-acetylmuramic acid --- Prevents formation of N-acetylmuramic acid --- precursor of Peptidoglycan . precursor of Peptidoglycan .

MOR: MOR: Inadequate transport into bacteria. Inadequate transport into bacteria.

Ph. k.:Ph. k.: Given orally, 40% bioavailability.Given orally, 40% bioavailability.

Half life 4 hrs. Renally excretedHalf life 4 hrs. Renally excreted

Spectrum of activity: Spectrum of activity: G +ve & G -ve G +ve & G -ve

Th. Uses: Th. Uses: Uncomplicated lower UTI in Uncomplicated lower UTI in women– single 3 g dose.women– single 3 g dose.

Safe in pregnancy.Safe in pregnancy.

Bacitracin: Bacitracin: Source: Source: Bacillus subtilis.Bacillus subtilis.

No cross resistance with other Antimicrobial drugs.No cross resistance with other Antimicrobial drugs.

Markedly nephrotoxic.Markedly nephrotoxic.

Th. Uses: Th. Uses: Not used systemicallyNot used systemically

Used topically as ointment on skin / MM , with Used topically as ointment on skin / MM , with polymyxin & neomycin for mixed bacterial flora.polymyxin & neomycin for mixed bacterial flora.

Saline solutions for irrigation of joints, wounds or Saline solutions for irrigation of joints, wounds or pleural cavity.pleural cavity.

Cycloserine:Cycloserine:Antibiotic -- streptomyces orchidaceus.Antibiotic -- streptomyces orchidaceus.

MOA:MOA: Structural analog of D-alanine ,blocks the incorporation Structural analog of D-alanine ,blocks the incorporation of D-Ala in to Peptidoglycan chain.of D-Ala in to Peptidoglycan chain.

Th. Uses:Th. Uses: 22ndnd line anti TB drug. line anti TB drug.

A/E:A/E: Serious CNS toxicity ---- headache, tremor, acute psychosis Serious CNS toxicity ---- headache, tremor, acute psychosis & convulsions. & convulsions.

Pharmacuetical Chemistry 2 Midterm

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