CHEMOTHERAPEUTIC AGENTS

in
INFECTIOUS DISEASES

Bernadette Halili-Mendoza, MD,FPPS

Instructor
 MICROORGANISMS
• Are of various types (bacteria, virus, fungal,
protozoans)
• Invades human tissues and are responsible for
afflicting body from mild to life-threatening
symptoms
• Body’s natural defense mechanism can and
sometimes unable to deal with pathogenic
invaders so pharmacologic treatment is
essential to resolve and promote recovery
ANTIBACTERIAL AGENTS
 ANTIBACTERIAL AGENTS
• SELECTIVE TOXICITY
– Selectively kill or attenuate the growth of the
pathogenic organism without causing excessive damage
to the host cells
– Common goal of drugs used to treat infectious diseases
– Organism may have distinctive structural or biochemical
feature allowing drug to selectively attack the invading
cell
• Agents used specifically against small unicellular organisms
are often referred to as antimicrobial drugs
• A.K.A antibiotics
– substances are used to kill other living organisms
– anti; (bios or life)
BACTERIA
• Unicellular microorganisms
• Has rigid cell wall surrounding the
bacterial cell
• Lacks a true nuclear membrane
• Invades human tissues to gain access to
a supply of amino acid, sugars and other
substances
BACTERIA
• NOT all bacteria are in the human body
are harmful
• Assist in the digestion of food and
synthesis of nutrients
• Can enter if defense mechanism of body
is compromised
 Pathogenic Effects of Bacteria
• They multiply competing with the host
cells for nutrients
• Releases toxic substances
• Can establish growth areas or colonies
that remain innocuous for extended
periods and becomes health threat
when host is immunocompromised
• NOT all bacteria are pathogenic
TYPES OF BACTERIA
Basic Principles in the Treatment
of Bacterial Infection
• Antibacterial spectrum
– Property of an antibiotic that determines
the clinical applications
– Broad spectrum antibiotics
• Effective against a variety of bacteria
• Eg tetracycline (gram + and - )
– Narrow Spectrum
• Eg. Isoniazid (bacilli)
• BACTERICIDAL
– Refers to drugs that typically kill or destroy
bacteria
• BACTERIOSTATIC
– Limits the growth and proliferation of
bacteria
❖Antibiotics are classified depending on
the mechanism of action
❖Depends on the dosage
Basic Mechanisms of Antibacterial Drugs

• Inhibition of bacterial cell wall synthesis

and function

• Inhibition of bacterial protein synthesis

• Inhibition of bacterial DNA/RNA function

PRIMARY SITES OF ANTIBACTERIAL EFFECT
INHIBITION OF BACTERIAL CELL WALL SYNTHESIS

• Membranes of bacteria are relatively firm and

rigid due to presence of PEPTIDOGLYCANS
– Protein polysaccharide structure
– Known as murein
– Cross-linked to one another within the cell wall to
provide rigidity and firmness
• MOA: destruct the cell membrane integrity
• Penicillins
• Cephalosporins
• Polymixins
BACTERIAL CELL WALL
INHIBITION OF BACTERIAL CELL WALL SYNTHESIS

• Mechanism of action of Antibiotics

– Penetrate and disrupt the architecture and
integrity of the surface membrane
– Act as detergents that breaks the
phospholipid bilayer apart creating gaps
and leaks
– Loss of integrity of the membrane leads to
rapid death
DRUGS THAT INHIBIT CELL WALL
SYNTHESIS
PENICILLINS
• First antibiotic
• Come in the form of natural and semi-
synthetic
• Known as beta lactam antibiotic (beta lactam
ring)
• MOA
– Exerts its effect by binding to specific
enzymatic proteins in the bacterial cell wall
PENICILLINS
• MOA
– Exerts its action by attaching to the
PENICILLIN-BINDING PROTEINS (PBP) to
inhibit its function
• Enzymatic proteins responsible for
normal synthesis of cell wall bacteria
– impairs the construction of Bacterial cell
wall
• Can be classified according to chemical
structure, spectrum of antibiotic activity or
pharmacokinetics
PENICILLINS
• Naturally occurring
– Pen G and Pen V
• Oral : narrow spectrum
• IM: broad spectrum
• Mainstay in the treatment of infections
• Drug of choice for in a diverse array of
clinical disorders
PENICILLINS
• Penicillinase Resistant Penicillins
– Overcome strains of bacteria containing the
enzyme penicillinase or beta lactamase
– Cloxacillin
– Dicloxacilli
– oxacillin
PENICILLINS
• Aminopenicillins (semi-synthetic)
– Amoxicillin
– Ampicillin
• Extended Spectrum Penicillins
– Piperacillin
– Ticarcillin
PENICILLINS
• ADVERSE EFFECT
– Allergic reactions
• primary problem
• Rashes, hives, itchiness, DOB
– Prolonged use
• CNS problem (confusion, hallucinations)
• Blood dyscrasias (hemolytic anemia;
thrombocytopenia)
• Gastrointestinal (vomiting, dyspepsia)
CEPHALOSPORINS
• Classified as beta lactam antibiotic
• Bactericidal effect (same with Penicillin)
• MOA
– Inhibiting of PBP resulting in an inadequate
peptidoglycan production
• Serves as an alternative to penicillin
• Drug of choice in certain type of UTI
CEPHALOSPORINS
• SUBDVISIONS (according to antibacterial activity)
– 1st generation cephalosporin
• Generally effective against gram (+) but may be
used for gram (–) bacteria
– 2nd generation cephalosporin
• More effective in gram (–) than the 1st gen but
can also with gram (+)
– 3rd generation cephalosporin
• Broadest spectrum of effectivity against gram (-)
with limited effect on gram (+)
– 4th generation cephalosporin
• Broadest antibacterial effect against gram (-)
and gram (+)
CEPHALOSPORINS
• 1st generation • 3rd generation cephalosporin
cephalosporin – Cefixime
– Cephalexin – Cefotaxime
– cefazolin – Ceftazidime
• 2nd generation – ceftriaxone
cephalosporin • 4th generation cephalosporin
– Cefaclor – cefepime
– Cefoxitin
– Cefuroxime
• Other Drugs inhibiting bacterial cell wall synthesis
– Aztreonam
– Bacitracin
– Polymixin B
– Vancomycin
AZTREONAM
• Beta lactam antibiotic but classified more of a
carbapenem
– Highly effective antibiotic for the treatment of
severe or high risk infection that is reserved for
MDR (multi-drug resistance)
• MOA
– Inhibits the synthesis and structure of the cell
membrane
• Effective in gram (-) like Pseudomonas and
Enterobacter aerogenes
• AE
– Skin rashes, redness and itching
BACITRACIN
• Group of polypeptide having similar effects
and properties
• MOA
– Inhibits bacterial cell wall synthesis by
inhibiting the incorporation of amino acid
and nucleic acid into the cell wall
• Broad range against gram (+) bacilli and cocci
• Applied topically to prevent and treat infection
from superficial wounds
• Usually combined with polymyxin and
neomycin
POLYMIXIN B
• Cationic compounds attracted to negatively charged
phospholipids in the cell wall of bacteria
• Penetrates and disrupts the architecture and integrity
of the surface of cell wall
• Acts as detergent that breaks the phospholipid bilayer
• Effective against gram (-) like E.coli and Salmonella
• AE
– Systemic administration : nephrotoxicity
• Used primarily as topical for local and superficial
infections with lesser adverse effect
VANCOMYCIN
• Binds directly to bacterial cell wall
precursor such as D-alanine impairing its
synthesis
• Effective against gram (+) bacilli and cocci
• AE
– Hypersensitivity
– Unpleasant taste to mouth
– Nephrotoxic severe adverse effects
– Ototoxicity
BETA LACTAMASE INHIBITORS
• Certain bacteria produces and enzyme beta
lactamase
– Binds to beta lactam drugs and destroys it
before it exerts its antibiotic effect
• Causes resistance to penicillin, cephalosporin
and others
• MOA
– Inhibits the beta lactamase enzyme from
destroying the effect of the antibiotic
• Typically combined with penicillins and others
• Clavulanate, sulbactam, tazobactam
DRUGS THAT INHIBIT BACTERIAL
PROTEIN SYNTHESIS
INHIBITION OF BACTERIAL CELL PROTEIN SYNTHESIS

• Bacteria must synthesize protein to carry out cellular

functions
• MOA
– Drugs enters the cell and binds to a ribose either
by blocking protein synthesis or cause a ribosome
to misread the mRNA code resulting in a
meaningless or nonsense protein
– This lack of appropriate protein impairs cell
transport and function
• Aminoglycosides (gentamicin, streptomycin)
• Tetracyclines
AMINOGLYCOSIDE
• Amikacin
• Gentamicin
• Neomycin
• Streptomycin
• MOA
– Binds irreversibly to some parts of the bacterial
ribosomes causing changes the protein
synthesis
– Altering in the ribosome’s ability to read the
mRNA genetic code resulting in improper
protein synthesis
AMINOGLYCOSIDE
• Effective against gram (-) like E. coli,
Pseudomonas and Salmonella
• Adverse effect
– Nephrotoxicity
• Most common adverse effect
– Ototoxicity
• Dizziness
• Ringing or fullness of ear
MACROLIDES
• Erythromycin
• Azithromycin
• Clarithromycin
• MOA
– Inhibits protein synthesis by binding to a
specific part of a ribosome impairing protein
synthesis by inhibiting the formation of peptide
bonds between the amino acids
– Cause the dissociation of tRNA units from their
binding site
MACROLIDES
• Broad spectrum against both gram (-) and (+)
• Alternative drug for penicillin allergy
• Seems to have an anti-inflammatory effect
especially with diseases of airway infection
• AE
– Given in high doses (bactericidal) can cause
GI problems
• Given at low dose (bacteriostatic) to have
lesser AE
TETRACYCLINE
• MOA
– Inhibits protein synthesis by binding to
several components of ribosomes causing
misreading of the mRNA code impairing the
peptide bonds
• Use to treat infection with chlamydia,
rickettsia and spirochetes
• Has as an anti-inflammatory and
immunomodulatory effect
• Doxycycline
TETRACYCLINE
• Adverse effects
– GI distress
– Hypersensitivity
– Photosensitivity
• Increases skin sensitivity to UV light
– Can form chemical complexes with Calcium
impairing the growth and development of
calcified tissues like bone and teeth
– Teeth discoloration
CHLORAMPHENICOL
• MOA
– Binds with the 50s subunit of bacterial
ribosomes inhibiting peptide bond
formation
• Effective on both gram (+) and gram (-)
• Used specific with typhoid fever and
osteomyelitis
• Adverse effects
– Bone marrow aplasia
• Most serious potential risk problem
CLINDAMYCIN
• Derived from lincomycin
• MOA
– Inhibits protein synthesis by binding to
the 50s subunit of ribosomes
• effective against gram (-) and gram (+)
• Alternative drug in the treatment of local
and systemic infection that cannot
tolerate penicillins and others
 DRUGS THAT INHIBITS BACTERIAL
RNA/DNA SYNTHESIS and FUNCTION
INHIBITION OF BACTERIAL DNA/RNA SYNTHESIS

• MOA
– Directly or indirectly interfere with the structure,
synthesis and function of DNA and RNA
– Impairs bacterial RNA/DNA function since they
have a greater affinity for these bacterial enzymes
• Fluoroquinolones
• Sulfonamides
• Bacteria needs to replicate their genetic material to
reproduce and function normally
FLUOROQUINOLONES
• Ciprofloxacin
• Levofloxacin
• Norfloxacin
• Ofloxacin
• Impairs the synthesis and replication of
bacterial RNA and DNA
FLUOROQUINOLONES
• MOA
– Inhibits 2 specific enzymes that affects the DNA
function
• DNA GYRASE
– Responsible for controlling the amount of
DNA winding (coils) in the bacterial cell
• TOPOISOMERASE IV
– Enzymatically separates two new DNA
strands that are formed during bacterial cell
wall division
– Impairs the DNA structure and function of bacterial
cell wall to grow and replicate
FLUOROQUINOLONES
• Effective against gram (-) and gram (+)
• E.coli, Klebsiella, Proteus
• Treatment of GI disorders, Osteomyelitis
• Treatment of STDs (gonorrhea)
• Adverse effect
– CNS toxicity (headache, dizziness)
– Tendinopathy
METRONIDAZOLE
• Exact mechanism is unknown
• Appears to be incorporated with the bacterial
cell that undergoes chemical reduction
• MOA
– Reduced metabolite of the drug interacts
with the bacterial DNA causing it to lose its
double helix characteristics leading to
disintegration of the DNA molecule and
loses its ability to replicate
METRONIDAZOLE
• Effective against anaerobic bacteria
(Bacteroides)
• Used in protozoans ( amoeba )
• Adverse effect
– Peripheral neuropathy
MUPIROCIN
• MOA
– Inhibits a specific enzyme responsible for
tRNA synthesis
• Used topically for Staphylococcal and
Streptococcal bacteria
• Can be administered via nasal spray to treat
local colonization of Staph aureus in the nasal
passages
RIFAMPICIN
• MOA
– Directly impairs DNA replication by binding
and inhibiting DNA dependent RNA
polymerase enzyme
• Treatment for Tuberculosis and Leprosy in
combination with other drugs
– TB: Rifampicin + Isoniazid
– Leprosy: Rifampicin + Dapsone
SULFONAMIDES
• Sulfadiazines
• Sulfamethizole
• MOA
– Interferes with bacterial nucleic acid
production by disrupting folic acid synthesis
in susceptible bacteria
ANTIVIRAL AGENTS
VIRUS
• One of the smallest precursor that
consists of only a nucleic acid core
surrounded by a protein shell
• Affects humans
• Can cause mild to severe symptoms
VIRUS characteristics
• Has a unique structure and function
• Consists of a core of viral DNA/RNA
• Core is surrounded by a protein shell (capsid)
• Does not contain cellular components necessary
to replicate or synthesize proteins
• It lacks ribosomes and endoplasmic reticulum
• Contains genetic codes (viral genome) that will
produce an additional virus
❖ Viruses invades host cell and eventually takes
control of the cell’s metabolic function
COMMON VIRUSES AFFECTING HUMANS
STEPS IN VIRAL REPLICATION
1. ADSORPTION
– Initially virus attaches and adsorp to the surface
of the host cell
2. PENETRATION and UNCOATING
- Virus enters the host either by passing directly
through the cell membrane or fuses with host cell
membrane releasing the viral genetic material
into the host
STEPS IN VIRAL REPLICATION
3. BIOSYNTHESIS
- once viral genetic material is inside virus now
takes control of the cell’s molecular synthesizing
machinery to initiate the biosynthesis of new viral
enzymes and proteins
4. MATURATION and RELEASE
- component parts (genetic code) are
assembled into mature virus and released to the
host cell
STEPS IN VIRAL REPLICATION
❖ steps in viral replication are important
pharmacologically because the antiviral
drugs may interrupt 1 or more steps
ANTIVIRAL DRUGS
ACYCLOVIR and VALACYCLOVIR
• It is effective against herpes virus infection (HSV-1 and
HSV-2)
• Principal drug to treat genital herpes in other mucosal
and cutaneous agents
• Varicella zoster infections
• MOA
– Inhibits viral DNA replication by inhibiting the DNA
polymerase enzyme
• Adverse effects
– Local irritation for topical uses
– Oral: headache, dizziness. GI disturbances
AMANTADINE and RIMANTADINE
• Used for the prevention and treatment of infections
caused by Influenza A
• Decreases the severity and duration of flu if initiated
on the 1st appearance of symptoms
• Used as an anti-Parkinson drug that blocks the effect
of excitatory neurotransmitters in the basal ganglia
• MOA
– Inhibits one of the early steps in virus replication by
blocking the uncoating and preventing the release
of viral nucleic acid within the host cell
– Inhibit the assembly of viral components thus
inhibits the final step in the replication process
AMANTADINE and RIMANTADINE
• Adverse effects
– CNS symptoms
• Confusion
• Loss of concentration
• Mood changes
• Dizziness
• seizures
OSELTAMIVIR
• Effective against influenza type virus Type A
and B
• Reduces the duration and severity of flu
symptoms if administered within 48hrs of
symptom appearance
• MOA
– Inhibits a specific enzyme (neuraminidase)
that influenza virus uses to complete its
biosynthesis and release
• Adverse effect
– GI disturbances
REMDESIVIR
• nucleoside analog used to inhibit the action of
RNA polymerase resulting in the termination
of RNA transcription and decreases viral RNA
production
• indicated for the treatment of adult and
pediatric patients aged 12 years requiring
hospitalization
• Usually given in 5 to 10 days of treatment
• Adverse effect
– hepatotoxicity
END OF SLIDE