Pharmacology for pharmacy students @2.pd

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Chemotherapy

Introduction
Chemotherapy
•Refers to the use of drugs against invading organisms (e.g.
bacteria, viruses, fungi) and cancer cells
Antimicrobial drug
•any agent, natural or synthetic, that has the ability to kill or
suppress microorganisms
Antibiotics
•Are chemicals that are produced by
one microorganism (bacteria,
fungi …) and suppress the growth of other microorganisms

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introduction …………..
Selective toxicity
•the ability of antibiotics to kill or suppress the growth of infecting
microbes without causing injury to the host cells
•This property of antibiotics makes them valuable drugs
How selective toxicity is achieved?
1.Differences in the cellular chemistry of mammals and microbes
E.g. bacteria have cell wall mammals don’t
2. There are biochemical processes critical to microbial well-being that
don’t take place in mammalian cells
E.g. bacteria synthesize folic acid, mammals don’t

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Use of Antimicrobials
•Empiric therapy
– treatment of an infection before specific culture information has been
reported or obtained
– initial – infecting organism not identified – single broad spectrum
agent
•Definitive therapy
–Treatment of an infection after the causative agent is identified
–microorganism identified – a narrow –spectrum low toxicity regiment
to complete the course of treatment
•Prophylactic therapy
–treatment with antibiotics to prevent an infection
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Effect of antimicrobials
•Static (inhibitory)
–arrest the growth or replication of the microorganism, but cannot kill
them.
e.g. Folate synthesis inhibition, protein synthesis inhibition

•Cidal (lethal)
–Is directly lethal to bacterial at clinically achievable concentrations
–Result from
•cell wall or cell membrane disruption
•inhibition of bacterial DNA replication or transcription
•irreversible inhibition of protein synthesis
E.g. β-lactams, floroquinolons & aminoglycosides

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6

Chemotherapeutic spectra
–Refers to the species of microorganisms affected by a particular
antimicrobial agent
1.Narrow spectrum: act on a single or a limited group of
microorganisms
2.Extended spectrum: affect gram positive bacteria and also
gram negative organism
3.Broad spectrum: affect wide variety of microbial species

Antimicrobials combinations
•simultaneous use of two or more antimicrobial agents is
recommended in specifically defined situations based on
pharmacological rationale

•However, selection of an appropriate combination requires an
understanding of the potential for interaction between the
antimicrobial agents
–Interactions may affect either the microbe or the patient

Antimicrobials combinations …
Indication for antimicrobial combinations
•To treat severe infection of unknown origin
•To treat polymicrobial infection
•To treat infections caused by resistant strains
•To enhance antimicrobial activity & broaden the antimicrobial
spectrum
•Preventing resistance to monotherapy
•Accelerating the rapidity of microbial kill
•To reduce toxicity

Antimicrobials combinations …
Clinical situations for which combination therapy is advised
include
antiretroviral therapy for AIDS (HAART), hepatitis B and C
Treatment of tuberculosis and leprosy
Fixed-dose combinations of antimalarial drugs
Treatment of Cryptococcus neoformans with flucytosine and
amphotericin B
The combination of a sulfonamide and an inhibitor of dihydrofolate
reductase, such as trimethoprim

Antimicrobials combinations …
Disadvantages of antibiotic combination
•Increased risk of toxic or allergic reactions
•Possible antagonism effect
•Increased risk of super-infections
•Increased cost to the patient
•Development of multidrug resistant strains

Resistance to Antimicrobial Drugs
•Drug resistance refers to unresponsiveness of a microorganism
to antimicrobial agents.

A)Natural resistance (innate resistance)
•Lack the metabolic process or the target site which is affected by a
particular drugs
•Does not pose significant clinical problem
E.g. Mycoplasma resistance treated by erythromycin

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Resistance to Antimicrobial Drugs….
B) Acquired resistance
•Had once been highly responsive, may become less responsive or
may lose sensitivity to the drug entirely or total non
responsive
•In some cases, resistance to multiple drugs develops
•Can render currently effective drugs useless
•Creating a clinical crisis and a constant need for new
antimicrobial agents

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Mechanisms to develop resistance
•Failure to reach the target
–reduced entry of antibiotic into pathogen
–enhanced export of antibiotic by efflux pumps
•The drug is inactivated
–release of microbial enzymes that destroy the antibiotic
–alteration of microbial proteins that transform pro-drugs to the
effective moieties
•The target is altered
–alteration of target proteins
–development of alternative pathways to those inhibited by the
antibiotic 14

Delaying emergency of resistance
Use antimicrobials conservatively and specifically in therapy
Select the drug according to the proven or anticipated known
susceptibility of the infecting strain
Use narrow spectrum antibiotic rather than broad spectrum antibiotics
when possible
Use antibiotics as prophylactically only in specific situation and for short
period of time
Avoid environmental contamination with antibiotics
Newer antibiotics should be reserved for situation in which older drugs
are dangerous or no longer effective
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Classifications of Antimicrobials
•Antimicrobial drugs can be classified in a number of ways
•These include:
1) By their chemical structure (for example, β-lactams or
aminoglycosides),
2) By their mechanism of action (for example, cell wall synthesis
inhibitors), or
3) By their activity against particular types of organisms (for example,
bacteria, fungi, or viruses).
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Antibacterial agents
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Mechanisms of action
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•Include:-
Beta-lactam antibiotics
Penicillins
Cephalosporins
 Monobactams
Carbapenems
Vancomycin
bacitracin and
Cycloserine
•Are bactericidal

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Cell wall synthesis
•Bacterial cell wall is composed of peptidoglycan units that
contains N-acetyl muramic acid (NAM) and N-acetyl
glucosamne (NAG)
•Cell wall synthesis starts with conversion of UDP-NAG into
UDP-NAM by enolpyruvate transferase.
•UDP-NAM then acquires the pentapeptide
•Alanine racemase and alanine-alanine ligase helps in the
formation of pentapeptide unit.

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•UDP is then removed from UDP-NAM-pentapeptide by
bactoprenol (membrane lipid carrier) and NAG is added to it
(which is carried by UDP-NAG).
•These all reactions occur in the cytoplasm.
•The resulting molecule formed is transported across the
plasma membrane by bactoprenol.
•Elongation of the peptidoglycan chain occurs with the help of
enzyme trans-glycosylase.
•Strength to peptidoglycan chain is provided by cross linking of
elongated chains with the help of trans peptidase.
Cell wall synthesis
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Cell wall synthesis inhibitors
Drugs Target
① Fosfomycin Enolpyruvate transferase
② Cycloserine Alanine racemase and alanine ligase
③ Bacitracin Dephosphorylation of bactoprenol
④ Vancomycin Trans glycosylase
⑤ Beta lactams Trans-pepetdase (last step)
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Beta lactam antibiotics
Contain beta lactam ring in their structure
–Penicillins
–Cephalosporins
–Carbapenems e.g imipenem
–Monobactams e.g aztreonam
Bacteria formed in the presence of these drugs are without
cell wall and die due to imbibition of water (cell wall
provides turgidity).

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Beta lactam antibiotics: MOA
Interfere with cell wall synthesis by binding to penicillin-
binding proteins (PBPs) which are located in bacterial cell
walls.
Inhibition of PBPs leads to inhibition of peptidoglycan
synthesis- cell death

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Mechanisms of Resistance
1. production of β-lactamase enzymes
 most important and most common
 hydrolyzes beta-lactam ring causing inactivation

2. Modification of target PBPs.
• responsible for methicillin resistance in staphylococci and penicillin
resistance in pneumococci.

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Mechanisms of Resistance…
3. Impaired penetration of drug to target PBPs.
• which occurs only in G- species, is due to impermeability of the
outer membrane that is present in G- but not in G+ bacteria.

4. The presence of an efflux pump
•Some organisms also may transport beta lactam antibiotics from
the periplasm back across the cell wall via an efflux pump

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Penicillins
•are bactericidal but can act only on dividing cells
•are not toxic to animal cells which have no cell wall
•The structure common to all penicillins is a β-lactam ring fused
with a thiazolidine nucleus

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Classification
• Based on their antimicrobial spectrum, penicillins can be
classified into three classes:
1. Natural penicillins: Penicillin G, Penicillin V
2. Anti-staphylococcal penicillins (penicillinase resistant
penicillins): Nafcillin, oxacillin, cloxacillin, dicloxacillin
3. Extended spectrum penicillins
•Aminopenicillins: ampicillin, amoxicillin
•Antipseudomonal penicillins: piperacillin, ticarcillin,
carbenicillin
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Natural penicillins
Absorption
Penicillin G
•Gastric juice at pH -2 rapidly destroys pen G
•Reduced acid secretion associated with aging accounts for better
absorption of pen G from GIT of older individuals
•Due to its acid labile nature, pen G is mostly administered by the
parenteral routes
Penicillin V
•is more stable in an acidic medium & is administered by the oral route
•better absorbed from the GIT after oral administration

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Natural penicillins …
Parenteral Administration of Penicillin G
•For prolonging and thereby reducing the frequency of injections
two mechanisms are available
1. Using Probenecid which blocks tubular secretion of pen G
2. Using depot formulations
oPen G procaine and pen G benzathine
•Are depot formulations of Pen G which release their
contents slowly and serum concentrations for long time

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Natural penicillins ….
Distribution
•Both Pen G & V are distributed widely throughout the body
•not readily enter the CSF when the meninges are normal but
can enter into the CSF during inflammations of the meninges

Excretion
–Eliminated rapidly from the body mainly by the kidney (through
tubular secretion & filtration)

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Natural penicillins ….
Therapeutic Uses
–Pen G is a drug of choice for infections caused by:
• Streptococci, Meningococci, gonococci, actinomycosis
• Non–β-lactamase producing staphylococci
• Treponema pallidum and non- β-lactamase producing
gram-negative anaerobic organism
–Penicillin V
•Penicillin V is used to treat mainly streptococcal infections
when oral therapy is appropriate and desirable

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Formulations of penicillin G
Formulation Description
Sodium Pen G A highly soluble salt
1 unit of activity 0.6 μg of pure sodium Pen G.
5 million units/vial, powder
Potassium Pen G Very soluble salt.
1 unit of activity 0.625 μg of pure potassium Pen G.
5, 20 million units/vial, powder
Procaine Pen G Much less soluble salt
Administered i.m. as a suspension of crystal particles that dissolve
slowly
1 unit of activity 1.0 μg of pure procaine penicillin
600, 000 units/ml, 1.2 m units/ 2ml syringe
Benzathine Pen G Even less soluble salt than procaine penicillin
Slowly absorbed after i.m. injection
One unit 0.75 μg of the pure substance.
600, 000 units/ml, 1.2 m units/ 2ml, 2.4 m units/4ml
Penicillin G aqueous (pre mixed injectable solution):1,2,3million units/50ml
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Penicillin G aqueous
•Penicillin-susceptible S. pneumoniae infections: pneumonia,
meningitis
•Streptococcal pharyngitis, endocarditis, skin and soft tissue
infection
•Neurosyphilis, neisseria meningitidis infections
•Gas gangrene (clostridium perfringens), actinomycosis
•Rat bite fever, listeria infections, anthrax, diphtheria
•Botulism (andjuctive to anti toxin)

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Benzathine penicillin G
URTI , group A streptococci: 1.2 million units IM stat
Secondary prevention of rheumatic fever: 1.2 million units
monthly or 600,000 units twice monthly
Secondary prevention of glomerulonephritis:1.2 million units
monthly or 600,000 units twice monthly
Primary, secondary and early latent syphilis (2.4 million units
IM stat) & late latent and tertiary syphilis for 3 weeks (once
weekly).

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Penicillin G procaine
•For moderately severe to severe infections: 600,000 to
1,000,000 units daily
Pneumococcal pneumonia
Staphylococcal infections
Streptococcal (for a minimum of 10 days)
Others: Yaws, Diphtheria, Anthrax

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Semisynthetic penicillins
•Ampicillin and amoxicillin (also known as aminopenicillins
or extended spectrum penicillins)
Spectrum:
–Gram-positive cocci (not staph), E. coli, H. influenzae
–Listeria monocytogenes (ampicillin)
–Borrelia burgdorferi (lyme) & H. pylori (amoxicillin)

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Spectrum of Activity
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Gram (+) cocci
Gram (+) bacilli
Gram (-) bacilli
Enterococci
 Streptococci
Listeria monocytogenes
Escherichia coli
Haemophilus inuenzae
Proteus mirabilis
Salmonella typhi
•Excellent activity vs. β-hemolytic streptococci, E. faecalis
•Good activity vs. S. pneumoniae, viridans streptococci,
haemophilus influenza
•Some activity vs. Proteus, Escherichia coli

Indications
–URTIs (sinusitis, pharyngitis, otitis media)
–Amoxicillin is employed prophylactically by dentists in
high-risk patients for the prevention of bacterial
endocarditis.
–Ampicillin is drug of choice for listeria meningitis
(cephalosporins are not effective effective) and UTI
caused by E. faecalis.
–Ampicillin is better effective for Shigella, but causes
more diarrhea.
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Anti-staphylococcal penicillins
Methicillin, nafcillin, oxacillin, cloxacillin
–are β-lactamase (penicillinase)-resistant penicillins.
–Excellent activity vs. MSSA; Good activity vs.
streptococci
–have minimal to no activity against gram-negative
infections, enterococci & Listeria.
–less effective against MOs susceptible to penicillin G
–Used for skin and soft tissue infections & serious
infections due to MSSA.
–Methicillin: causes interstitial nephritis.
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Anti-staphylococcal penicillins…
–MRSA and MRSE are resistant to all beta lactam
antibiotics except ceftaroline and ceftobiprole.
–Methicillin resistance is developed due to the formation
of alternative penicillin binding proteins that have less
affinity for the drugs.
–Can be treated by vancomycin, daptomycin, clindamycin,
or linezolid.
–Food  their absorption and should be given after food.
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Antipseudomonal penicillins
They are effective against many gram-negative bacilli, but
not against Klebsiella because of its constitutive
penicillinase.
–Carboxypenicillins (Carbenicillin<Ticarcillin)
–Ureidopenicillins (Azlocillin< Mezlocillin< Piperacillin)
Newest class
More active against streptococci, Haemophilus
species, pseudomonas spp .
Used with beta lactamase inhibitors and with
aminoglycosides.
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Antipseudomonal penicillins…
Piperacillin
–Piperacillin extends the spectrum of ampicillin to include
most strains of P. aeruginosa, Enterobacteriaceae (non–
β-lactamase producing), many Bacteroides spp., and E.
faecalis.
–Formulation of piperacillin with tazobactam extends the
antimicrobial spectrum to include penicillinase-producing
organisms (for example, most Enterobacteriaceae and
Bacteroides species).

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Antimicrobial spectrum of Piperacillin
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Antipseudomonal penicillins…
Piperacillin/tazobactam (iv)
–Excellent activity vs. E. coli, Klebsiella
–Good activity vs. Pseudomonas, Citrobacter,
Enterobacter
–Uses
Nosocomial infections: pneumonia, intra-abdominal
infections (E. faecalis and B. fragilis), urinary tract
infections.
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β-Lactamase Inhibitor Combinations
•Several formulations combine a β -lactam antibiotic with a β-lactamase
inhibitor
Clavulanic acid
is combined with amoxicillin for oral administration (AUGMENTIN)
and with ticarcillin for parenteral administration (TIMENTIN)
Sulbactam
combined with ampicillin for IV or IM use (UNASYN)
Tazobactam
combined with piperacillin as a parenteral preparation (ZOSYN)

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The in vitro growth of E. coli in the presence of amoxicillin, with
and without clavulanic acid.
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Adverse effects of penicillins
•Penicillins are remarkably nontoxic & safest of the antibiotics
•Most of the serious adverse effects are due to hypersensitivity
•Allergic reactions include:
–Anaphylactic shock, urticaria, pruritus bronchospasm, angioedema,
laryngeal edema, and hypotension
–Late onset immune-mediated reactions to β-lactam antibiotics may
manifest as eosinophilia, hemolytic anemia, interstitial nephritis, or
serum sickness
•All penicillins are cross-sensitizing
–In general, patients with a history of allergic reaction to one β-lactam
antibiotic should avoid all other β-lactam antibiotics except aztreonam

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Cephalosporins
•are semisynthetic antibiotics derived from products of various
microorganisms, including Cephalosporium and Streptomyces
•Closely related both structurally and functionally to penicillins
•the same mode of action as penicillins
•affected by the same resistance mechanisms with pencillins.
•more resistant than the penicillins to certain β-lactamases.
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•The cephalosporins are classified into generations according to their
antibacterial spectrum and stability to β-lactamases
–1
st
generation cephalosporins
–2
nd
generation cephalosporins
–3
rd
generation cephalosporins
–4
th
generation cephalosporins
–Advanced generation cephalosporins
•Urinary excretion is the major elimination path for most
cephalosporins.
–When prescribing cephalosporins to patients with renal failure,
practitioners must consider dose reduction or dose interval
extension
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1
st
generation cephalosporins
•Act as penicillin G substitutes.
•Excellent activity against MSSA, streptococci
•Modest activity against P. mirabilis, E. coli, and K.
pneumoniae.
•Isolates of S. pneumoniae resistant to penicillin are also
resistant.
•Most oral cavity anaerobes like peptostreptococcus are
sensitive, but the Bacteroides fragilis group is resistant.

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Antimicrobial spectrum
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Staphylococcus aureus*
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Gram (+) cocci
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Gram (–) rods
*Methicillin-resistant staphylococci are resistant
Penicillin-resistant streptococci are resistant

1
st
generation…
Indications
–Skin and soft tissue infections (S. pyogenes and MSSA)
–Respiratory tract infections, otitis media
–Genitourinary tract infections, including acute prostatitis
–Acute bacterial endocarditis prophylaxis.
–Perioperative surgical prophylaxis (cefazolin)
Cefazolin: 250 mg - 2 g IV Q8 hrs
Cephalexin: 250mg - 1g PO Q6hrs
Cefadroxil: 500mg- 1g PO Q 12 hrs

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2
nd
generation cephalosporins

•display greater activity against 3 additional gram-negative
organisms:
H. influenzae
Enterobacter aerogenes
some Neisseria Species
•activity against gram-positive (cocci) organisms is weaker
•Cephamycins (cefotetan & cefoxitin) cover anaerobes (for
example, bacteroides fragilis).
•no drugs enter the CNS, except cefuroxime

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Anti bacterial spectrum
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Gram (+) cocci
Staphylococcus aureus (weak)
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Gram (–) cocci
Neisseria gonorrhoeae
Gram (–) rods
Enterobacter aerogenes
Escherichia coli
Haemophilus inuenzae
Klebsiella pneumoniae
Proteus mirabilis
Anaerobic organisms**
**Cefoxitin and cefotetan

2
nd
generation…
Drugs Tips
Cefuroxime
(IV/PO)
•Higher activity against Haemophilus influenzae
•respiratory infections including CAP, skin structure
infections, gonorrhea, bone and joint infections
•Cefuroxime sodium (parentral), 750 mg Q 8hr
•Cefuroxime axetil 250mg twice daily (oral)
Cefoxitin &
Cefotetan
(IV)

•Skin infections, UTI, gas gangrene
•Surgery infection prophylaxis (colorectal, non
perforated appendectomy, hysterectomy, ruptured
viscus)
Cefaclor &
Cefprozil
(PO)
•may be useful in treating otitis, sinusitis, and RTI.
•More activity against H. infleuenzae and E. coli by
cefaclor 59

3
rd
generation
•Excellent activity against streptococci, H. influenza, Proteus, E.
coli, Klebsiella, Serratia, Neisseria
•Good activity against MSSA
less potent than 1
st
G cephalosporins against MSSA
•Some activity against Citrobacter, Enterobacter
•lack activity against L. monocytogenes and penicillin-resistant
pneumococci, which may cause meningitis.

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Spectrum
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Gram (+) cocci
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Gram (–) cocci
Neisseria gonorrhoeae
Gram (–) rods
Enterobacter aerogenes
Escherichia coli
Haemophilus inuenzae
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens
Most enter CNS; important in empiric management of meningitis and sepsis
Important in the treatment of infectious diseases

3
rd
generation: parenteral
Ceftriaxone
–has the longest t
1/2 of any cephalosporin
–allowing for once-daily dosing for most indications.
–BID has been effective for patients with meningitis.
–largely eliminated in the bile, safe in kidney disease.
–IM, IV: Usual dose: 1 to 2 g every 12 to 24 hours, depending
on the type and severity of infection
–Combining calcium with ceftriaxone can form potentially
fatal precipitates.

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3
rd
generation: parenteral
Cefotaxime (metabolized to desacetyl-cefotaxime)
–activity against B. fragilis is poor
–has the shortest serum half-life (1 hour)
oUncomplicated infections: IM/IV: 1 g q 12 hours
oModerate-to-severe infections: IM/IV: 1-2 g q 8 hrs
oLife-threatening infections: IV: 2 g q 4 hours

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3
rd
generation: parenteral…
Ceftazidime (excellent activity against pseudomonas)
–is 1/4 to 1/2 as active against G
+
MOs as is cefotaxime
–activity against staphylococci is particularly poor.
–activity against the Enterobacteriaceae is similar to
ceftriaxone
–renally eliminated (dose adjustment in renal dysfunction).
–250mg-2g iv/im Q 8 or Q12 hr

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3
rd
generation: parenteral…
Ceftolozane
–Ceftolozane is a structural analogue of ceftazidime
–has enhanced activity against Pseudomonas, including activity
against strains resistant to ceftazidime through β-lactamase
overexpression.
–It has similarly weak activity to ceftazidime against gram-
positive organisms.
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3
rd
generation: oral
•are active against streptococci, H. influenzae (including beta-
lactamase producing strains), and M. catarrhalis.
•more active than the other oral cephalosporins against
enteric G -ve bacilli, like E. coli, P. mirabilis, & Klebsiella.
•Used for RTIs, otitis media & UTI
Cefixime & ceftibuten : 400mg daily
Cefpodoxime: 100-200mg twice daily
Cefdinir: 300mg twice daily
Cefditoren: 200-400mg twice daily

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3
rd
Generation indications
•Gram negative septicemia & other serious Gm –ve infections
•Pseudomonas aeruginosa infections (Ceftazidime)
•Gram negative meningitis: Cefotaxime, Ceftriaxone.
•Gonorrhea - Single shot of Ceftriaxone is drug of choice
•Complicated urinary tract infections, pyelonephritis
• Osteomyelitis – Ceftriaxone
•Lyme disease – ceftriaxone
•Community-acquired pneumonia
•Streptococcal endocarditis
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Ceftriaxone
•Bacillary dysentery (250 mg Stat)
•Pneumonia (1gm for 5-7days)
•Typhoid fever (1gm for 5-7days)
•Bacterial septicemia (1gm for 5-7days)
•Pelvic inflammatory disease - 250mg stat
•Meningitis (2gm for 5-7days)
•Complicated gonococcal conjunctivitis 1gm stat
•Uncomplicated gonococcal infection -125-250mg stat
68

4
TH
Generation Cephalosporin
69
Gram (+) cocci
Streptococci
Staphylococci: MSSA
Gram (-) cocci
Neisseria gonorrhoeae
Gram (-) rods
Enterobacter aerogenes
Escherichia coli
Haemophilus infuenzae
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
•Even wider spectrum
•Resistant to most beta-lactamases
•Enters CNS
Cefepime & cefpirome
•encephalopathy at high doses

Cefepime indications
Indication Regimen
Febrile neutropenia •2 g every 8 hours
Intra-abdominal infections,
complicated, severe (in
combination with
metronidazole)
•Due to P. aeruginosa: 2 g every 8 hours
for 7 to 10 days
•Not due to P. aeruginosa: 2 g every 8 to
12 hours for 7 to 10 days
Pneumonia •Due to P. aeruginosa: 2 g every 8 hours
for 10 days
•Not due to P. aeruginosa: 1 to 2 g every
8 to 12 hours for 10 days
Skin and skin structure
infection, uncomplicated
(moderate to severe)
•2 g every 12 hours for 10 days
Urinary tract infections,
complicated and
uncomplicated
•Mild-to-moderate: IM, IV: 0.5 to 1 g every
12 hours for 7 to 10 days
•Severe: IV: 2 g every 12 hours for 10 days
70

Advanced generation: Ceftaroline fosamil
•gram-negative activity comparable to cefotaxime.
•has enhanced gram-positive activity: MRSA and penicillin-
resistant S. pneumoniae.
•over 95% of MRSA and penicillin-resistant S. pneumoniae
isolates are inhibited by ceftaroline.
•Important gaps in coverage include P. aeruginosa, extended-
spectrum β-lactamase (ESBL)-producing Enterobacteriaceae,
and Acinetobacter baumannii.

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Ceftaroline fosamil…
•Excellent activity against streptococci, MSSA, MRSA, H.
influenzae, Proteus, E. coli, Klebsiella, Serratia
•Some activity vs. Citrobacter, Enterobacter
•Indications
Pneumonia, community-acquired: IV: 600 mg every 12 hours
for 5 to 7 days
Skin and skin structure infection: IV: 600 mg every 12 hours
for 5 to 14 days
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Cephalosporin/β-Lactamase inhibitors
Ceftolozane/tazobactam; Ceftazidime/avibactam
–Effective in the treatment of resistant Enterobacteriaceae
and multidrug-resistant Pseudomonas aeruginosa.
–Effective against some β-lactamase–producing bacteria
(for example, select strains of ESBLs).
–narrow gram-positive and very limited anaerobic activity.

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Indications, iv only
Ceftazidime/avibactam
(2.5g/vial)
•Intra-abdominal infections,
complicated: 2.5 g tid in
combination with metronidazole
for 5-14 days.
•Pneumonia, hospital-acquired
and ventilator-associated
(HAP/VAP): 2.5 g tid, 7-14dys.
•UTIs, complicated (including
pyelonephritis): 2.5 tid for 7-14
days.
Ceftolozane/tazobactam
(1.5g/vial)
•Intra-abdominal infections
(complicated): 1.5 g tid for
4-14 days in combination
with metronidazole.
•UTIs (complicated,
includes pyelonephritis):
1.5 g tid for 7 days.

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Major differences between cephalosporin generations
class Activity
against
G-ve
bacteria
Activity
against
G+ve
bacteria
Resistan
ce to β-
lactamas
es
Distributio
n to CSF
1
st
generation low Highest low poor
2
nd
generation higher Higher higher poor

3
rd
generation higher Low higher Good
4
th
generation highest Higher highest good

Cephalosporins…
76

Cephalosporins…
77

Cephalosporins…
78
Side effects..
Ceftriaxone: neonatal kernicterus (use cefotaxime), biliary
pseudolithiasis.
cefazolin and cefotetan—can induce a state of alcohol
intolerance.
cefotetan and ceftriaxone— can cause bleeding tendencies.
Hemolytic Anemia (Rarely): immune-mediated

Carbapenems
•Carbapenems are synthetic β-lactam antibiotics that differ in
structure from the penicillins in that the sulfur atom of the
thiazolidine ring has been externalized and replaced by a
carbon atom.
Imipenem
Meropenem
Doripenem
Ertapenem

79

Imipenem
Antibacterial spectrum
–Imipenem resists hydrolysis by most β-lactamases, but not
the metallo-β-lactamases.
–This drug plays a role in empiric therapy because it is
active against β-lactamase–producing gram-positive and
gram-negative organisms, anaerobes, and P. aeruginosa.
80

Antimicrobial spectrum of imipenem
*Methicillin-resistant staphylococci are resistant
**Includes penicillinase-producing strains
81

Antimicrobial spectrum of imipenem..
82

Therapeutic uses of imipenem…
–UTI and lower respiratory infections
–intra-abdominal and gynecological infections
–skin, soft tissue, bone, and joint infections
–especially useful for the treatment of infections caused by
cephalosporin-resistant nosocomial bacteria.
–for empirical treatment of serious infections in
hospitalized patients who have recently received other β-
lactam antibiotics.
–Imipenem/cilastatin: 250/250, 500/500mg powder for inj.

83

Meropenem & Doripenem
Meropenem
–Compared to imipenem, it is somewhat less active against
gram-positive organisms (particularly Enterococcus) and
more active against gram negative organisms.
–preferred for treatment of meningitis
Doripenem
–has a spectrum of activity that is similar to that of
meropenem, with greater activity against some resistant
isolates of Pseudomonas.
84

Ertapenem
•Ertapenem differs from imipenem and meropenem
by having a longer t
1/2 that allows once-daily dosing &
by having inferior activity against Enterococcus, P.
aeruginosa, and Acinetobacter spp.
•Its activity against Enterobacteriaceae and anaerobes makes
it useful in intra-abdominal and pelvic infections.
85

Meropenem-vaborbactam
•It is approved for the treatment of complicated urinary tract
infections including pyelonephritis.
•This combination agent has activity against
Enterobacteriaceae producing a broad spectrum of β-
lactamases, except metallo-β-lactamases.
86

Carbapenems
87

Aztreonam (monobactam)
•Has antimicrobial activity directed primarily against gram-
negative pathogens, including the Enterobacteriaceae and P.
aeruginosa active only against gram-negative aerobic
bacteria.
•Aztreonam is not absorbed from the GI tract and hence must
be administered parenterally (IM or IV) for systemic therapy.
•Eliminated by the kidneys, primarily unchanged.
88

Aztreonam…
•Lacks cross-allergenicity with other β-lactams (except
ceftazidime).
safe alternative who are allergic to beta lactams
•Uses: Nosocomial infections: pneumonia, UTIs
•Relatively nontoxic, but it may cause phlebitis, skin rash, and,
occasionally, abnormal liver function tests.
89

Vancomycin (glycopeptide)
Mechanism of action:
–Binding at the D-ala-D-ala muramyl pentapeptide to
sterically hinder the trans-glycosylation reactions (indirectly
preventing trans-peptidation) involved in elongation of
peptidoglycan chains.
–Does not interfere with PBPs
90

Vancomycin
Spectrum:
–active against aerobic and anaerobic gram-positive bacteria
Including: MRSA, penicillin-resistant streptococci, ampicillin-
resistant enterococci, clostridium difficile (backup drug).
G+organisms intrinsically resistant to vancomycin include
Lactobacillus, Leuconostoc, Pediococcus, & Erysipelothrix.
Essentially all species of gram-negative bacilli and
mycobacteria are resistant to glycopeptides.
91

Vancomycin…
*Includes methicillin-resistant strains.
**Oral vancomycin only for C. difficile.
92

Vancomycin…
Resistance:
–Vancomycin-resistant staphylococcal (VRSA) and
Enterococcal (VRE) strains are emerging.
–Enterococcal resistance involves change in the muramyl
pentapeptide “target,” such that the terminal D-ala is
replaced by D-lactate.
93

Vancomycin indications
•Bacteremia and endocarditis due to staphylococcal
endocarditis
For MRSA or severe penicillin allergy
•Endocarditis caused by viridans streptococci
in patients who are allergic to penicillin
•In combination with amino glycosides for enterococcal
endocarditis (for penicillin allergy or penicillin-resistant
isolates).

94

Vancomycin indications…
•Skin and soft-tissue infections, bone and joint infections
•Pneumonia (community-acquired /nosocomial)
•Meningitis (nosocomial meningitis by staphylococci)
•Clostridium difficile colitis (oral formulation)
•Surgical prophylaxis for procedures with high risk of MRSA
•Vascular catheter infections
95

Vancomycin…
Pharmacokinetics:
–Used IV (IM pain) and orally in colitis (not absorbed)
–Enters most tissues (e.g., bone), but not CNS
–Eliminated by renal filtration (dose adjustment).
Side effects:
–“Red man/ Red neck syndrome” (histamine release)
–Ototoxicity (usually permanent, additive with other drugs)
–Nephrotoxicity (mild, but additive with other drugs)

96

Lipoglycopeptides
Telavancin, Oritavancin, and Dalbavancin
–improved target site binding due to their structure.
–telavancin & oritavancin also disrupt membrane potential.
improve activity and minimize selection of resistance.
–Hence, more potent than vancomycin and may have
activity against vancomycin-resistant isolates.

97

Oritavancin and dalbavancin
Spectrum: Similar activity to vancomycin
Highly protein bound
Extremely long t
1/2
Once-weekly dosing (dalbavancin)
single-dose therapy for skin infections (Oritavancin)
Uses: acute bacterial skin and skin structure infections
Renal excretion is very slow and dosage adjustment is not
required in moderate renal dysfunction.
98

Telavancin
•Similar activity to vancomycin with activity against some
vancomycin-resistant strains of Enterococcus.
•is considered an alternative to vancomycin in treating
acute bacterial skin and skin structure infections
hospital-acquired pneumonia caused by resistant gram-
positive organisms, including MRSA.
•Higher nephrotoxicity relative to vancomycin, QT
prolongation, Avoid in pregnancy
•Clinical use limited by its toxicity

99

Bacitracin
•Bacitracin inhibits the synthesis of the bacterial cell wall
Inhibits dephosphorylation of bactoprenol
•Active against broad array of gram-positive and gram-
negative organisms
Neisseria, H. influenzae, and T. pallidum, Actinomyces,
Fusobacterium and others
•Enterobacteriaceae, Pseudomonas, Candida spp., and
Nocardia are resistant to the drug.
100

Bacitracin…
Available in ophthalmic and dermatologic ointments
uses
–prevention and treatment of skin and soft-tissue
infections (topical)
–ophthalmic infections
ADR: nephrotoxicity with parenteral use

101

Daptomycin (Lipopeptides)
•binds to bacterial membranes, resulting in depolarization, loss
of membrane potential, and cell death.
•Conc. dependent killing
•bactericidal antibiotic selectively active against aerobic,
facultative, and anaerobic gram-positive bacteria.
•Retains activity against some VRE
•Protein bound: limited CNS penetration
•Inactivated by pulmonary surfactant; not effective for
pneumonia.
•Renal elimination & rare myositis and rhabdomyolysis
102

Daptomycin..
103

Daptomycin..
Indications (alternative to other agents, such as vancomycin
or linezolid)
–Skin and soft-tissue infections
–Staphylococcal and streptococcal bacteremia
– Vancomycin-resistant enterococcal infections
–dosed IV once daily.
104

Polymyxins—Bactericidal Cell
Membrane-Disrupting Agents
•The antimicrobial activities of polymyxin B and colistin are
similar & restricted to gram-ve bacteria, primarily aerobes.
•Most Pseudomonas, Acinetobacter, & Enterobacteriaceae are
susceptible, except for Proteus and Serratia spp.
•are surface-active amphipathic agents that act as cationic
detergents.
•They interact strongly with phospholipids and disrupt the
structure of cell membranes.

105

Colistin (polymyxin E) (IV, inhaled)
•Serious infections due to MDR gram-negative organisms
•Prevention of cystic fibrosis exacerbations (inhaled).
•Good activity against Acinetobacter, E. coli, Klebsiella,
Pseudomonas, including multidrug-resistant strains.
•Prodrug; complex pharmacokinetics with renal and nonrenal
elimination.
•Substantial nephrotoxicity and neurotoxicity.
106

Polymyxin B (IV, topical)
•Serious infections due to MDR gram-negative organisms.
•Topical treatment/prevention of skin and soft-tissue
infections.
•Polymyxin B sulfate is available for ophthalmic, otic, & topical
use in combination with other compounds.
•Similar activity and toxicity as colistin
•Nonrenally eliminated; does not achieve high urinary levels
107

2. Protein synthesis inhibitors
•Bacteria have two ribosomal subunits
–30S and 50S
–The 30S subunit binds mRNA in initiation and holds growing
peptide chain.
–The 50S subunit accepts / translocates charged tRNAs.
•are divided into two groups: bacteriostatic and bactericidal.
–Chloramphenicol, macrolides, clindamycin (Lincosamides), and
tetracyclines are bacteriostatic
–Aminoglycosides are bactericidal

Tetracyclines
•Are broad spectrum antibiotics which are synthesized by a number
of streptomyces species
•Tetracyclines consist of four fused rings with a system of conjugated
double bonds.
•Substitutions on these rings alter the individual pharmacokinetics
and spectrum of antimicrobial activity.
•Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit of
bacterial ribosomes.
•Block the attachment of aminoacyl tRNA to mRNA–ribosome
complex (−static).
109

Tetracyclines…
110
A B C D
.
There is no OH at position 6 on methacycline, doxycycline &
minocycline

Classification of TTCs
1. Short acting (half life 6-8 hours)
Tetracycline, chlortetracycline, Oxytetracycline
Have low lipid solubility, absorption decrease with food,
eliminated by renal excretion
2.Intermediate acting: (half life 16 hours) Demeclocycline
Have moderate lipid solubility, absorption decrease with food,
eliminated by renal route
3.Long acting: (half life18-24 hours) doxycycline and
minocycline
are more lipophilic and most active
absorption not affected with food, eliminated by Hepatic
route
4.Longest acting: Tigecycline newest TTC (half life-36 hours)

111

Tetracyclines…
Spectrum: broad spectrum
–gram-positive and gram-negative bacteria
–protozoa, spirochetes, mycobacteria, and atypical species.
–intrinsically are more active against gram-positive than
gram-negative microorganisms.
–useful as first-line therapy for infections caused by
rickettsiae, mycoplasmas, and chlamydiae.
–all strains of Pseudomonas aeruginosa are resistant
Note: TTCs affect both prokaryotic & eukaryotic cells
–But are selectively toxic to bacteria, why?? 112

Antibacterial spectrum…
113
Gram (+) cocci
Staphylococcus aureus
(including methicillinresistant strains)
Streptococcus pneumoniae
Gram (+) bacilli
Bacillus anthracis
Gram (–) cocci
Gram (–) rods
Brucella species*
Vibrio cholerae
Yersinia pestis
Anaerobic organisms
Clostridium perfringens
Clostridium tetani
Spirochetes
Borrelia burgdorferi
Leptospira interrogans
Treponema pallidum
Mycoplasma
Mycoplasma pneumoniae
Chlamydia
Chlamydia species
Other
Rickettsia rickettsii
Many gram –ve and P. aeruginosa develop resistance
*(tetracycline + gentamicin)

Tetracyclines
•Indications
predominantly for the treatment of rickettsia infections,
including Rocky Mountain spotted fever, cholera, Lyme
disease, and infections caused by Chlamydia species and
Mycoplasma pneumonia.
Malaria prophylaxis & Amoebiasis
for the treatment of inflammatory acne vulgaris.
Helicobacter pylori infection in combination with others.
Demeclocycline for SIADH
Minocycline has  activity for staphylococci & Acinetobacter
114

Tetracyclines…..
Pharmacokinetics:
–The primary route of elimination for most tetracyclines is
the kidney.
–Half life of doxycycline and minocycline longer than others
–Doxycycline is the safest in impaired renal function.
–Therapeutic concentrations in the brain and CSF can be
achieved with minocycline.
–Chelators: tetracyclines bind divalent cations (Ca
2+,
Mg
2+,
Fe
2+
), which ↓ their absorption
115

Tetracyclines…..
Side effects:
–Tooth enamel dysplasia and possible ↓ bone growth in
children (avoid < 8yrs of age)
–Phototoxicity (demeclocycline, doxycycline)
–GI distress (NVD)
–superinfections leading to candidiasis or colitis
–Vestibular dysfunction (minocycline)
–Have caused liver dysfunction during pregnancy at very high
doses (contraindicated).
116

Tigecycline (glycylcycline)
reversibly binding to the 30S ribosomal subunit
exhibits broad-spectrum activity that includes
–methicillin-resistant staphylococci (MRSA)
–multidrug resistant streptococci
–vancomycin-resistant enterococci (VRE)
–extended-spectrum β-lactamase–producing gram
negative bacteria, many anaerobic organisms.
–not active against Pseudomonas species.
117

Tigecycline…
Indications
–serious complicated skin and skin structures infections
and intra-abdominal infections.
–Increased risk of death in pooled analysis; reserve as
alternative therapy.
118

Tigecycline….
PK
–achieves low plasma concentrations.
poor option for bloodstream infections.
–the primary route of elimination is biliary/fecal.
–dose  in severe hepatic dysfunction but not in renal
impairment.
ADR
–associated with significant nausea and vomiting.
–Acute pancreatitis, including fatality, has been reported

119

Macrolides
•Includes:
–Erythromycin ..parent drug
–Azithromycin & Clarithromycin … semisynthetic
derivatives
•These structural modifications improve acid stability
and tissue penetration and broaden the
spectrum of activity
120

Mechanism of Action
•are bacteriostatic agents that inhibit protein synthesis by binding
reversibly to 50S ribosomal subunit
•Are bacteriostatic but can be bactericidal at higher
concentrations for susceptible microbes
•Macrolide should not be given together with CAF, since they
compete for the same site.
•Resistance to Macrolides can occur:
–Efflux pumps, Metabolizing enzymes
–Modification of the 50s ribosomal subunit

121

122
Antibacterial spectrum…
122
Gram (+) cocci
S. pyogenes
S. pneumoniae
Cornybacterium diphtherae
Gram (+) bacilli
Gram (-) cocci
Bordetella pertussis
Campylobacter jejuni
Haemophilus inuenzae
Legionella pneumophila
Treponema pallidum
Spirochetes
Mycoplsama
Mycoplasma pneumoniae
Ureaplasma urealyticum
Chlamydia pneumoniae
Chlamydia psittaci
Chlamydia trachomatis
Chlamydia
Gram (-) bacilli
Moraxella catarrhalis
Neisseria gonorrhoeae
Mycobacterium avium complex
Other

Erythromycin (iv, po, topical)
•Effective against many of the same organisms as penicillin G
•Considered as an alternative in patients with penicillin allergy
•Good activity against Mycoplasma, Chlamydia, Legionella,
Campylobacter, Bordetella pertussis, C. diphtherieae
•Some activity against S. pneumoniae, S. pyogenes, H. influenzae
•Staphylococci are not reliably sensitive to erythromycin
•Indications: Erysipelas and cellulitis, Ophthalmia neonatorum,
Diphtheria, Pertussis
•Adult: 250 – 500 mg QID

123

Clarithromycin (po)
•Similar to erythromycin, with improved activity against
streptococci and staphylococci
•Good activity against Moraxella catarrhalis, Chlamydia spp, H.
pylori, and non-tuberculous mycobacteria
•Somewhat less active than erythromycin against H. influenzae
•Adult: 250 – 500mg twice daily

124

Clarithromycin…
Indications
–Erysipelas and cellulitis
–Community-acquired pneumonia
–Acute exacerbations of chronic bronchitis
–Helicobacter pylori gastritis (in combination with other
agents)
–Mycobacterium avium treatment and prophylaxis
125

Azithromycin (iv, po)
•less active than erythromycin against streptococci and
staphylococci.
•Azithromycin is far more active against respiratory pathogens
such as H. influenzae and Moraxella catarrhalis.
•Extensive use of azithromycin has resulted in growing
Streptococcus pneumoniae resistance.
•Has anti-inflammatory properties and long t
1/2, ~48 h
•Adult: 500 mg – 2g stat/once daily

126

Azithromycin…
Indications
–Community-acquired pneumonia
–Acute exacerbations of chronic bronchitis
–Otitis media
–Bacterial pharyngitis
–Chlamydia
–Mycobacterium avium treatment and prophylaxis
–Treatment of sexually transmitted diseases, especially
during pregnancy
127

Telithromycin, ketolide (po)
•Similar to azithromycin with activity against macrolide-resistant
streptococci and staphylococci.
•Indication: Community-acquired infection
•Due to risk of severe hepatotoxicity, reserve as alternative
therapy.
•Telithromycin’s dose in adults is 800 mg orally once daily.

128

PK of macrolides
•Erythromycin base is destroyed by gastric acid (thus, either
enteric-coated tablets or esterified forms).
•Others are stable in stomach acid and are readily absorbed.
•Food interferes with the absorption of erythromycin and
azithromycin but can increase that of clarithromycin.
•Azithromycin should be given 1 h before or 2 h after meals
•Telithromycin is administered orally without regard to meals.
129

PK of macrolides…
•Inhibitors of cytochrome P450 system.
DDI with theophylline, statins, and numerous antiepileptics
•Azithromycin (active) & Erythromycin and its metabolites:
excreted in the bile.
•Clarithromycin (along with its metabolite) mainly excreted in
the urine
Need dose adjustment in renal impairment.
130

Macrolides…
Side effects:
•Gastrointestinal distress (erythromycin, azithromycin >
clarithromycin) due to stimulation of motilin receptors
•Reversible deafness at high doses
•Increased QT interval
•Cholestatic jaundice: estolate form of erythromycin
•Severe hepatotoxicity: telithromycin

131

DI of macrolides
132

Fidaxomicin
•macrocyclic antibiotic, similar structure with macrolides
•has a unique mechanism of action.
acts on the sigma subunit of RNA polymerase
disrupt bacterial transcription, terminating protein
synthesis and resulting in cell death.
•has a very narrow spectrum of activity limited to gram-
positive aerobes and anaerobes.
•minimal systemic absorption (primarily remains in GIT)
ideal for the treatment of C. difficile infection

133

Clindamycin (Lincosamide)
•Not a macrolide, but has the same mechanisms of action and
resistance.
•Active against G+ cocci (including MRSA) & Anaerobes (B.
fragilis, C. perfringens).
•Also has some activity against toxoplasma, pneumocystis &
plasmodium.
•Essentially all aerobic gram-negative bacilli are resistant.
•The drug is employed primarily for anaerobic infections
outside the CNS (it doesn’t cross the BBB).

134

Clindamycin…
Indications
–can be used for the treatment of gynecological infections,
intra-abdominal infections, and skin and bone infections.
–Topical preparations of the drug are used for the treatment
of acne.
ADR
–Diarrhea is common with clindamycin.
–It has a high risk for causing C. difficile infections
(psaudomembranous colitis).

135

Chloramphenicol
•Binds reversibly to the bacterial 50S ribosomal subunit and
inhibit the activity of peptidyltransferase
peptide bond formation is inhibited.
chloramphenicol also can inhibit mitochondrial protein
synthesis (erythropoietic cells are particularly sensitive).
•Resistance usually is caused by a plasmid-encoded
acetyltransferase that inactivates the drug.
•Active against many types of microorganisms including
enterococci, mycoplasma, chlamydiae, rickettsiae, spirochetes,
and anaerobes.

136

Chloramphenicol…
•Primarily bacteriostatic, but bactericidal against H. influenzae,
Neisseria meningitidis, and S. pneumonia
•P. aeruginosa is resistant to even at very high concentrations.
•Resistant strains of Shigella & Salmonella typhi are prevalent.
Because of risk of fatal toxicities, reserve as alternative
–Currently a backup drug for infections due to
- B. fragilis, Rickettsia
- Bacterial meningitis (H. influenzae, N. meningitidis, and
S. pneumonia)
–Strains of V. cholerae have remained largely susceptible

137

Chloramphenicol…
PK
–Available in oral, iv, and topical (e.g., ophthalmic) forms.
–Good tissue distribution, including CSF
–Metabolized by hepatic glucuronidation, and dose
reductions are needed in liver dysfunction and in neonates
–Secreted into breast milk (avoided in breastfeeding
mothers).
–Inhibition of cytochrome P450
138

Chloramphenicol…
Side effect
–Dose-dependent bone marrow suppression common
–Aplastic anemia rare (1 in 35,000): with G6PD deficiency
–“Gray baby” syndrome in neonates (↓ glucuronosyl
transferase and inadequate renal excretion of
unconjugated drug)
–Jarisch-Herxheimer reactions may occur after therapy for
syphilis, brucellosis & typhoid fever.

139

Quinupristin/Dalfopristin (30:70)
•The two streptogramins bind to a separate site on the 50S
bacterial ribosome.
Dalfopristin
- enhance the binding of quinupristin at its target site.
- disrupts elongation by interfering with the addition of new
amino acids to the peptide chain.
Quinupristin
- prevents elongation (translocation) and causes release of
incomplete peptide chains
Thus, they synergistically interrupt protein synthesis.
140

Quinupristin/Dalfopristin…
•active against gram-positive cocci and organisms responsible
for atypical pneumonia (e.g., M. pneumoniae, Legionella spp.,
and C. pneumoniae)
•bactericidal against streptococci and many strains of
staphylococci
•bacteriostatic against Enterococcus faecium.
•not effective against E. faecalis and gram-negatives.

141

Quinupristin/Dalfopristin…
Uses(reserved for treatment of serious infections)
–infections caused by vancomycin resistant staphylococci
(VRSA) and enterococci (VRE), as well as other drug
resistant, gram-positive cocci.
–Vancomycin-resistant Enterococcus faecium infections
(bacteriostatic).
–nosocomial pneumonia and infections caused by MRSA

142

Quinupristin/Dalfopristin…
PK
–Both are available intravenously.
–It does not achieve therapeutic concentrations in CSF.
–Both compounds undergo hepatic metabolism, with
excretion mainly in the feces.
Side effects
–Venous irritation
–Hyperbilirubinemia (25%)
–inhibits the cytochrome CYP3A4 isoenzyme

143

Oxazolidinones (linezolid and tedizolid)
Mechanism:
–bind to the bacterial 23S ribosomal RNA of the 50S
subunit, thereby inhibiting the formation of the 70S
initiation complex and translation of bacterial proteins.
Spectrum:
–gram positive organisms including MRSA, VRSA, VRE, and
drug-resistant pneumococci.
–poor activity against most gram-negative aerobic or
anaerobic bacteria.

144

Antimicrobial spectrum of oxazolidinones
145

Oxazolidinones…
•Bacteriostatic against enterococci and staphylococci but may
be bactericidal against streptococci.
•not recommended as first-line treatment for MRSA
bacteremia (bacteriostatic).
•Linezolid is an alternative to daptomycin for VRE.
•Resistance in enterococci and staphylococci is most
commonly due to point mutations of the 23S rRNA.

146

Oxazolidinones…
oUses: treat infections caused by drug-resistant G+ organisms.
Linezolid (IV, PO)
•Skin and soft-tissue infections (MSSA, MRSA)
•Pneumonia (community-acquired due to S. pneumoniae
and nosocomial due to S. aureus).
•Vancomycin-resistant enterococcal infections
•Nocardiosis
•Extensive drug-resistant tuberculosis
Tedizolid (IV, PO): Skin and soft-tissue infections
147

Oxazolidinones…
PK:
–well absorbed after oral administration.
–No dose adjustments are required for either agent for
renal or hepatic dysfunction.
Side effects:
–GI upset, bone marrow suppression (platelets), 7-10 days
–Mitochondrial toxicities (long term use, 6 weeks)
peripheral neuropathy, optic neuritis, and lactic acidosis
–MAO-A and B inhibitor
148

Aminoglycosides
Includes
–Gentamicin, Netilmicin, amikacin
–kanamycin, tobramycin, neomycin & streptomycin
Chemistry
At physiologic pH
•these drugs are polycations
•can’t readily cross membranes
–Are not absorbed from GIT, do not enter CSF
–And are rapidly excreted by the kidney
149

Aminoglycosides
•cause the 30S subunit of the completed ribosome to misread
the genetic code & incorporation of wrong amino acid (−cidal)
•accumulated intracellularly in microorganisms via an O
2-
dependent uptake → anaerobes are innately resistant
•Have
concentration dependent and post antibiotic effect.
•Synergistic actions occur for infections caused by enterococci
(with penicillin G or ampicillin) and P. aeruginosa (with an
extended spectrum penicillin or 3
rd
generation cephalosporin).

150

Aminoglycosides…
•Their transport is enhanced if used along with cell wall
synthesis inhibitors like penicillins.
•Resistance to these drugs develops due to the formation of
inactivating enzymes which acetylate, phosphorylate or
adenylate the aminoglycosides.
•All aminoglycosides except amikacin and netilmicin are
susceptible to these enzymes.
•Thus amikacin and netilmicin may be effective against organisms
resistant to other aminoglycosides.
151

•are effective for the majority of
aerobic gram-negative bacilli, including
those that may be multidrug resistant,
such as Pseudomonas aeruginosa,
Klebsiella pneumoniae, and
Enterobacter sp.
Aminoglycosides spectrum of action
152

Gentamicin
•parenteral, ophthalmic, and
topical administration
•Vestibular > cochlear toxicity
•Toxicity primarily renal and
reversible.
Uses
•UTI
•Peritonitis
•Endocarditis in combination
with a cell-wall active agent
•Plague
•Tularemia

153

Tobramycin
•Similar to gentamicin, with better activity against P. aeruginosa.
•contrast to gentamicin, tobramycin shows poor activity in
combination with penicillin against many strains of enterococci.
•Most strains of E. faecium are highly resistant.
•ineffective against mycobacteria.
•Cochlear ≈ vestibular toxicity
Uses
–UTI
–Lung infections, including cystic fibrosis exacerbations
–Nosocomial sepsis of unknown origin

154

Amikacin
•has the broadest antimicrobial activity of the group.
•similar to tobramycin, with activity against some gram-negative
bacilli resistant to other aminoglycosides
•active against M. tuberculosis, including streptomycin-resistant
strains and atypical mycobacteria
•less active than gentamicin against enterococci and should not
be used for this organism.
•Cochlear > vestibular toxicity
155

Amikacin…
Uses
–UTI
–Lung infections, including cystic fibrosis exacerbations
–Nosocomial sepsis of unknown origin
–Mycobacterial infections
–used in the treatment of severe gram-negative infections,
especially those resistant to gentamicin or tobramycin.
156

Streptomycin
•generally is less active than other members of the class
against aerobic gram-negative rods.
•Similar to gentamicin, with activity against some gentamicin-
resistant enterococci.
•The combination of penicillin G and streptomycin is effective
for enterococcal endocarditis.
•Activity against Mycobacterium tuberculosis
•Vestibular > cochlear toxicity
•Vestibular toxicity is irreversible
157

Streptomycin…
Uses
–Endocarditis in combination with a cell-wall active agent
–Tuberculosis
–Plague
–Tularemia
–severe cases of brucellosis
Streptomycin has been replaced by gentamicin for most
indications because the toxicity of gentamicin is primarily renal
and reversible, whereas that of streptomycin is vestibular and
irreversible.
158

Neomycin
•PO, topical; urologic irrigation
•Similar activity to gentamicin but only used topically.
•Strains of P. aeruginosa are resistant to neomycin
•Can cause skin rash
•Uses
Minor skin infections
Bowel preparation prior to intra-abdominal surgery
Bladder irrigation along with polymyxin B
Oral neomycin is used for hepatic encephalopathy

159

Paromomycin (aminosidine)
•Activity similar to other aminoglycosides but has particularly
notable anti-parasitic activity.
Cryptosporidia infection
Intestinal amebiasis
Leishmaniasis
•Uses
IM use for visceral leishmaniasis
Topical use for cutaneous leishmaniasis
•Side effect: diarrhea, nausea, vomiting

160

Kanamycin
•Kanamycin is amongst the most toxic aminoglycosides, and
there are few indications for its use.
•Its primary remaining indication is for treatment of
extensively drug-resistant tuberculosis.
•even in this condition, less-toxic alternatives are generally
preferred.

161

PK of aminoglycosides
•Are polar compounds, not absorbed orally and variable
distribution into tissues.
•Concentrations achieved in CSF are inadequate (even in
inflamed meninges).
•More than 90% of the parenteral aminoglycosides are
excreted unchanged in the urine.
•Neomycin is primarily excreted unchanged in the feces.
•Renal elimination proportional to GFR, and major dose
reduction needed in renal dysfunction.

162

Aminoglycosides…
163

3. Nucleic Acid Inhibitors: Quinolones
•Naldixic acid is the first quinolone.
•Its use is limited to urinary and GI infections because of:
–low potency, narrow spectrum and high frequency of
bacterial resistance.
•Fluorination of the quinolone structure  floroquinolones
with high potency
better tissue penetration and
good tolerability.
•They are bactericidal

Generation Drug Names Spectrum
1st
nalidixic acid Gram- but not
Pseudomonas species
2nd
Norfloxacin,
ciprofloxacin
Enoxacin, ofloxacin
Gram- (including
Pseudomonas species), some
Gram+ (S. aureus) and some
atypicals
3rd
levofloxacin
sparfloxacin
moxifloxacin
gemifloxacin
Same as 2
nd
generation with
extended Gram+ and
atypical coverage
4th
*trovafloxacin

Same as 3
rd
generation with
broad anaerobic coverage
165

floroquinolones …
Mechanism of action
•have different targets for G-ve (DNA gyrase) and G+ve
organisms (topoisomerase IV), resulting in rapid cell death.
Inhibition of DNA gyrase prevents the relaxation of positively
supercoiled DNA.
Inhibition of topoisomerase IV interferes the separation of
replicated DNA during cell division.
•Resistance is increasing (target alteration).

floroquinolones …
•are more efficacious than cotrimoxazole or oral β-lactams for
the treatment of UTIs.
•reserved for complicated cystitis or pyelonephritis when
possible, particularly when resistant to Cotrimoxazole.
•typically not used for the treatment of
S. aureus or enterococcal infections
Syphilis
Neisseria gonorrhoeae due to resistance (limited use).

Norfloxacin (po)
•Good activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella,
Shigella
•Some activity vs. Pseudomonas
•low serum concentration limits its usefulness even for UTIs and
GI infections.
Uses
–UTI, prostatitis
–Traveler’s diarrhea
o400 mg twice daily
168

Ciprofloxacin
•Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia,
Salmonella, Shigella
•Good activity vs. Pseudomonas
•Some activity vs. S. aureus, streptococci
•Good bioavailability (~70%) and tissue distribution
•Renal and non-renal elimination
Oral: 500 mg every 12 hours
IV: 400 mg every 12 hours

169

Ciprofloxacin…
Uses
–UTI
–Prostatitis (4-6 wks)
–Traveler’s diarrhea
–Intra-abdominal infections (with metronidazole)
–Pseudomonas infections
–Anthrax, tularemia
170

Levofloxacin
•Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia,
Salmonella, Shigella, streptococci, H. infleuenzae, Legionella,
Chlamydia.
•Good activity vs. Pseudomonas, S. aureus
•Good bioavailability and tissue distribution
•Renal elimination
•S-isomer of Ofloxacin (for otitis media)
250, 500, 750mg op/iv once daily
171

Levofloxacin…
Uses
–UTI
–Prostatitis
–Respiratory tract infections, drug-resistant pneumococci
–STD (Chlamydia trachomatis and Haemophilus ducreyi)
–Traveler’s diarrhea
–Intra-abdominal infections (with metronidazole)
–Pseudomonas infections
172

Moxifloxacin
•Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia,
streptococci, H. influenzae, Legionella, Chlamydia
•Good activity vs. S. aureus, Bacteroides fragilis
•Good bioavailability and tissue distribution
•Renal and non-renal elimination
•QT prolongation
•Does not concentrate in urine and is not indicated for the
treatment of UTIs.
Oral, IV: 400 mg every 24 hours

173

Moxifloxacin…
Uses
–Respiratory tract infections (for CAP, but not hospital
acquired pneumonia due to poor coverage of P.
aeruginosa).
–Intra-abdominal infections
–2
nd
line agent for drug-susceptible tuberculosis

174

Gemifloxacin & Gatifloxacin
•have a similar spectrum of activity to moxifloxacin, with
enhanced potency against gram-positive organisms and poor
activity versus Pseudomonas.
•They are less active than moxifloxacin against B. fragilis.
Gemifloxacin (oral only): acute exacerbation of chronic
bronchitis & CAP.
Gatifloxacin (ophthalmic) for bacterial conjunctivitis.

175

Delafloxacin
•has enhanced gram-positive activity, including MRSA,
Enterococcus spp., Staphylococcus and Streptococcus spp.
•Also active against & Mycobacteria spp, bacteroides fragilis,
Enterobacteriaceae and Haemophilus influenza.
•Active against P.aeruginosa
•Use: skin and skin structure infections
Oral: 450 mg every 12 hours for 5 to 14 days
IV: 300 mg every 12 hours for 5 to 14 days
176

Antimicrobial spectrum
177

Fluoroquinolones…
Pharmacokinetics:
–Iron, calcium limit their absorption
–Eliminated mainly by kidney by filtration and active
secretion (inhibited by probenecid)
–Reduce dose in renal dysfunction except moxifloxacin
(dose  liver disease).
178

Fluoroquinolones…
Side effects:
–Tendonitis, tendon rupture
–Phototoxicity, rashes
–CNS effects (insomnia, dizziness, headache)
–Contraindicated in pregnancy and in children (inhibition
of chondrogenesis)
–Ciprofloxacin inhibits CYP450 1A2/3A4 (theophylline,
tizanidine, warfarin, ropinirole, duloxetine, caffeine,
sildenafil, and zolpidem).

179

Folate Antagonists
180
Sulphonamides are competitive
enzyme inhibitors so inhibition
is reversible
Sulfa drugs, including cotrimoxazole, are bacteriostatic

Sulfonamides
•Sulfonamides alone are limited in use because of multiple
resistance
•Some activity against S. pyogenes, S. pneumoniae, S. aureus, H.
influenzae, E. coli, Nocardia
•Sulfasalazine is a prodrug and metabolized by colonic
bacteria in to 5-aminosalicylic acid (ulcerative colitis) and
sulfapyridine (rheumatoid arthritis).
Not absorbed
181

Sulfonamides…
Drugs Indications
Sulfisoxazole (PO) •Lower UTIs
•Otitis media (with erythromycin)
Sulfadoxine (PO) •Prophylaxis and treatment of malaria
(with pyrimethamine)
Sulfadiazine (PO) •Toxoplasmosis (with pyrimethamine)
•Reasonable CSF penetration
•Higher risk of crystalluria, requires
hydration
Sulfacetamide
(ophthalmic)
•Treatment of ocular infections
•High penetration into ocular fluids
•Silver sulfadiazine &
Mafenide (topical)
•Prevention of infection in burn patients
182

Pharmacokinetics
•Sulfonamides are hepatically acetylated (conjugation)
•Renally excreted metabolites cause crystalluria (older drugs),
precipitate at acidic or neutral PH
•Inhibition of CYP2C9: warfarin & phenytoin
•High protein binding
Drug interaction (Warfarin & methotrexate)
Kernicterus in neonates (avoid in third trimester)
C/I in newborns and infants less than 2 months of age
183

Side effects
Sulfonamides
–Hypersensitivity (rashes, Stevens-Johnson syndrome)
–Hemolysis in G6PD deficiency
–Phototoxicity
Trimethoprim or pyrimethamine
–Bone marrow suppression (leukopenia)
–hyperkalemia, especially at higher doses (trimethoprim)

184

Cotrimoxazole
•Trimethoprim/sulfamethoxazole (1:5), 480,960mg
•The combination was selected because of the synergistic
activity and the similarity in the half-lives of the two drugs
•Generally administered orally
•IV may be utilized in patients with severe PCP
•Readily crosses the blood–brain barrier

185

186

Uses of cotrimoxazole
Bacteria:
–DOC in Nocardia, Listeria (backup)
–G-ve infections (E. coli, Salmonella, Shigella, H. influenzae)
–Gram-positive infections (Staph., including community
acquired MRSA, Strep.)
Fungus: Pneumocystis jiroveci (back-up drugs are
pentamidine and atovaquone)
Protozoa: Toxoplasma gondii (sulfadiazine +
pyrimethamine)

187

Cotrimoxazole..
188

Metronidazole
•In anaerobes, converted to free radicals by ferredoxin, binds
to DNA and other macromolecules, bactericidal
•Antiprotozoal: Giardia, Trichomonas, Entamoeba
•Antibacterial: strong activity against most anaerobic gram-
negative Bacteroides species, Clostridium species (DOC in
pseudomembranous colitis), Gardnerella, and H. pylori
•It lacks activity against aerobic bacteria.
•Acquired resistance is uncommon.

189

Metronidazole…
Uses
–Clostridium difficile colitis
–Empiric coverage of anaerobic organisms, as in intra-
abdominal and skin and soft-tissue infections
–H.pylori gastritis (in combination with other agents)
–Bacterial vaginosis
190

Metronidazole…
–Pk
Iv or oral
Excellent absorption
 Wide distribution, including CNS
Hepatic elimination
–CYP inhibitor: drug interactions with warfarin
–Side effects: metallic taste, disulfiram-like effect,
peripheral neuropathy with prolonged use

191

Antimycobacterial Agents:
Drugs for Tuberculosis

Tuberculosis
•is a leading infectious killer globally which is caused by
Mycobacterium tuberculosis
Risk factors
•Patients with underlying immune suppression (e.g., renal failure,
cancer & immunosuppressive drug treatment)
•Children under 2 years of age & oldies above the age of 65
years
•HIV/AIDS patients, health professionals
•Individuals living in poorly ventilated areas & with malnutrition

193

Overview of Antituberculosis Therapy
Objective
to eliminate symptoms of active disease and to prevent relapse
–kill those tubercle bacilli that are actively dividing as well as those
that are resting
Mycobacteria are resistant to most antibiotics because:
Grow slowly
Mycobacterial cells can also be dormant
Lipid-rich mycobacterial cell wall is impermeable to many agents
Mycobacterial species are intracellular pathogens- inaccessible to
drugs that penetrate these cells poorly

194

Complications of chemotherapy
•a number of factors can complicate therapy of TB including:
–Limited information about the MOA of anti-TB drugs
–Vigorous resistance developing ability of the mycobacteria
–Intracellular location of mycobacteria
–Chronic nature of the disease
–Patient compliance
•Longer period therapy
•Multiple medications
•Many drug interactions

195

•Drugs used in the treatment of TB can be divided into two
First-line agents
•Have the greatest level of efficacy with an acceptable degree of
toxicity
•Includes: isoniazid (H), rifampin (R), ethambutol (E), streptomycin (S) &
pyrazinamide (Z)
•majority of patients with TB can be treated successfully with these
drugs
Second-line agents
•reserved for resistant cases of TB
•less efficacious & highly toxic than 1
st
line drugs
•Includes: moxifloxacin or gatifloxacin, ethionamide, aminosalicylic
acid, cycloserine, amikacin, kanamycin, capreomycin & linezolid
196

Phases of Treatment
There are two phases:
1.Intensive (initial) phase
Consists of 4 or more drugs
Duration
8 weeks for new cases & 12 weeks for re-treatment cases
The drugs must be swallowed daily under direct observation
(DOT)
Rapid killing of actively growing and semi dormant bacilli.
It renders the patient non infectious
Regimen: 2HERZ
197

Phases of Treatment …..
2.Continuation phase
Immediately follows the intensive phase
Consists of 2 or 3 drugs
Duration is 4 – 6 months
Except for re-treatment cases drugs must be collected every
month.
Eliminates bacilli that are still multiplying.
Reduces failures and relapses.
Regimen: 4HR
198

Anti TB Drugs
Drugs MOA AE
Isoniazid
(H)
Inhibits the
synthesis of mycolic
acids
Hypersensitivity reaction
Peripheral neuritis
Memory loss, seizure
Hepatotoxicity
Rifampicin
(R)
Bind to RNA
polymerase - inhibit
RNA synthesis
Hypersensitivity reaction
GI intolerance
Hepatotoxicity
Inducer of CP450: enhance
metabolism of PI, NNRTI, digitalis,
BDZP Pyrazinami
de (Z)
Interfere with
biosynthesis of
mycolic
acid
gastrointestinal intolerance
Hepatotoxicity
Gout

Anti TB Drugs ….
Ethambuto
l (E)
Inhibit arabinosyl
transferase (inhibit
synthesis of
mycobacterial cell
wall)

•Optic neuritis -  visual acquity
- inability to discriminate red
and green
• Hyperuricemia - Due to 
Excretion of uric acid
•Rash
Streptomy
cin (S)
Protein synthesis
inhibitor
•Nephrotoxic
•Ototoxixty
•Hypersensitivity reactions

Isoniazid (INH)
Mechanism
•a prodrug activated by a mycobacterial catalase–
peroxidase (KatG).
•targets the enzymes ketoenoyl 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.
201

Isoniazid…
Antibacterial spectrum
•Isoniazid is specific for treatment of M. tuberculosis,
although M. kansasii may be susceptible at higher drug
concentrations.
•Most nontuberculous mycobacteria (NTM) are resistant.
•particularly effective against rapidly growing bacilli
•also active against intracellular organisms.
For prophylaxis, INH is used alone.
202

Isoniazid…
Resistance: follows chromosomal mutations
1)mutation or deletion of KatG (producing mutants
incapable of prodrug activation): main resistance
2)varying mutations of the target proteins, or
3)overexpression of the target enzyme InhA.
Cross-resistance may occur between isoniazid and
Ethionamide via InhA.
203

Isoniazid…
Pharmacokinetics
•readily absorbed after oral administration.
•Absorption is impaired if isoniazid is taken with food,
particularly high-fat meals.
•diffuses into all body fluids, cells, & caseous material.
•concentrations in the CSF and serum are similar.
•undergoes N-acetylation and hydrolysis, resulting in
inactive products and renal elimination.
204

Isoniazid…
ADR
•Hepatitis (age-dependent)
•Peripheral neuritis (use vitamin B6)
•Transient memory loss, psychosis
•Sideroblastic anemia (use vitamin B6)
•SLE in slow acetylators (rare)
INH Is an analog or pyridoxine (vitamin B6).
205

Rifampin
Mechanism
•Inhibits DNA-dependent RNA polymerase (nucleic acid
synthesis inhibitor).
•equally effective against intra- and extra cellular bacilli.
•the only bactericidal drug active against dormant bacteria
in solid caseous lesions.

206

Rifampin…
Spectrum and use (broader antimicrobial activity than INH )
•Tuberculosis and NTM, such as M. kansasii and MAC.
•Leprosy, Brucellosis
•Prophylaxis of meningococcal disease & H. influenzae
meningitis.
•Combination therapy in selected cases of staphylococcal
endocarditis or osteomyelitis, especially those caused by
staphylococci “tolerant” of penicillin.
207

Rifampin…
PK
•Absorption is adequate after oral administration.
•Distribute to all body fluids and organs.
•10% -20% of blood conc. are attained in the CSF .
•taken up by the liver & undergoes enterohepatic recycling.
•Elimination primarily through the bile and into the feces
•Urine, feces, & other secretions have an orange-red color.
208

Rifampin…
ADR
•Safest in renal failure & the least toxic anti TB drug.
•nausea, vomiting, and rash are common.
•Hepatitis, especially in combination with other anti-TB
agents, in alcoholics, or preexistent liver disease
•Induction of P450: replacement of rifampin with
rifabutin.

209

Rifampin…
210

Pyrazinamide
•Its mechanism seems to be similar to INH but the exact
site is not known: weakly bactericidal
•Enzymatically hydrolyzed by pyrazinamidase to pyrazinoic
acid (active form).
•Some resistant strains lack the pyrazinamidase enzyme.
•Most active against slowly replicating bacteria an in the
acidic media (intracellular sites and at the sites of
inflammation) has best sterilizing activity

211

Pyrazinamide…
•Most of the clinical benefit occurs early in treatment;
discontinued after 2 months of a 6-month regimen.
•Distributes throughout the body, penetrating the CSF.
•dosing frequency is reduced to 3 x/week at low GFR.
•Removed by hemodialysis; redose after each session
•Adverse effects: non gouty arthralgia, hyperuricemia,
hepatotoxicity.
212

Ethambutol
•is bacteriostatic and specific for mycobacteria.
•Inhibits synthesis of arabinogalactan (cell-wall component)
by inhibiting arabinosyl transferase.
•used in combination with pyrazinamide, isoniazid, and
rifampin pending culture and susceptibility data.
•may be discontinued if the isolate is determined to be
susceptible to isoniazid, rifampin, and pyrazinamide.
213

Ethambutol…
PK
•distributes well throughout the body except CSF.
•excreted in the urine: parent drug and its metabolite.
• dose and frequency reduction in renal failure
Side effect
•dose-dependent reversible retrobulbar neuritis → ↓ visual
acuity and red-green discrimination.
•Uric acid excretion: gout

214

Rifabutin
•used as rifampin replacement to avoid drug interactions of
rifampin with other medications, especially in HIV
coinfection (PIs or NNTIs ).
•Treatment of disseminated MAC in patients with AIDS
•Weaker CYP3A induction than rifampin
•Concentrations higher in tissue than plasma
•t
1/2 ~ 45 h
215

Rifabutin..
ADR
•Neutropenia in 25% of patients with HIV
•Primary reasons for therapy discontinuation include rash,
GI intolerance, and neutropenia.
•Uveitis and arthralgia in patients receiving doses > 450 mg
daily.
216

Rifapentine
•Long t
1/2 of ~ 14–18 h, allowing more intermittent dosing
(1–2 times weekly).
•97% protein binding
•Moderate CYP3A induction
•In combination with isoniazid, rifapentine may be used
once weekly in patients with LTBI and in selected HIV-
negative patients with minimal pulmonary TB.

217

2
nd
line drugs
•Levofloxacin or
Moxifloxacin
•Bedaquiline
•Linezolid
•Clofazimine
•Cycloserine or
Terizidone
•Delamanid
•Imipenem-cilastatin or
Meropenem
•Amikacin or Streptomycin
•Ethionamide or Prothionamide
•p-aminosalicylic acid (PAS)
In general, these agents are less effective and more toxic
than the first-line agents.
218

Special population
1.Co-management of HIV and Active TB Disease
It is recommended that TB patients who are living with HIV
should receive at least the same duration of TB treatment as
HIV negative TB patients
TB treatment should be started first, followed by ART as soon
as possible and within the first 8 weeks of starting TB
treatment
The recommended first-line ART regimens for TB patients are
those that contain efavirenz (EFV)

219

Special population…
2. Pregnancy
•With the exception of streptomycin, the first line anti-TB drugs
are safe for use in pregnancy: streptomycin is ototoxic to the
fetus and should not be used during pregnancy.
3. TB and Leprosy
•Rifampicin will be common to both regimens and it must be
given in the doses required for TB.

220

Special population…
4. Treatment of patients with renal failure
•Avoid streptomycin and Ethambutol
•Give 2HRZ/4HR.
5. Treatment of patients known liver disease
•Do not give pyrazinamide because this is the most
hepatotoxic anti-TB drug.
•Recommended regimens are: 2HERS/6HE or 2HES/10HE

221

Treatment of Extrapulmonary TB
•Of the EPTB, lymphatic, pleural, and bone or joint disease are
the most common, while pericardial, meningeal and
disseminated (miliary) forms are more likely to result in a fatal
outcome.
•TB meningitis: 9-12 months of treatment
•TB of bones or joints: 9 months of treatment
222

Drug resistant TB
•Drug resistant TB: M. tuberculosis that is resistant to one of the
first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, or
ethambutol.
•MDR-TB: M. tuberculosis that is resistant to at least isoniazid and
rifampin, and possibly additional chemotherapeutic agents.
•Extensively drug-resistant tuberculosis (XDR-TB): M.
tuberculosis that is resistant to at least isoniazid and rifampin (as in
MDR-TB) and is also resistant to fluoroquinolones and either
aminoglycosides (amikacin, kanamycin) or capreomycin, or both.
223

Drugs for Leprosy
•Leprosy is a chronic infectious disease which
predominantly affects peripheral nerves and the skin
•Other tissues, like the eye, mucosa of the upper
respiratory tract, muscles, bone and testis can also be
involved.
•It is caused by Mycobacterium leprae.
•Infection with M. leprae occurs through the nasal mucosa
from droplet infection.

224

Dapsone
•structurally related to the sulfonamides
•inhibits dihydropteroate synthase in the folate synthesis.
•It is bacteriostatic for M. leprae, and resistant strains may be
encountered.
•well absorbed & distributed throughout the body (high conc in
the skin).
•The parent drug undergoes hepatic acetylation.
•Both parent drug and metabolites are eliminated in the urine.

225

Dapsone…
•Also doc for dermatitis herpetiformis & Alternative for
Pneumocystis jiroveci infection and prophylaxis
ADR
•Gastrointestinal irritation, fever, skin rash
•G6PD deficiency should be tested prior to use.
•Hemolysis at doses of 200–300 mg of dapsone per day
•methemoglobinemia
•infectious mononucleosis like syndrome

226

Clofazimine
•is a phenazine dye
•Its mechanism of action may involve binding to DNA
•Its redox properties may lead to the generation of
cytotoxic oxygen radicals that are toxic to the bacteria.
•Only bacteriostatic against M. leprae
•Due to its anti-inflammatory action it can be used for
lepra reaction.
•erythema nodosum leprosum may not develop
227

Clofazimine…
ADR
•GI problems are encountered in 40%–50% of patients.
•Abdominal pain due to crystal deposition in cavities and
tissues
•Body secretion, eye, and skin reddish-black discoloration
occur in most patients
228

Rifampin
•It is the bactericidal and most effective drug used in
leprosy.
•It prevents development of resistance to Dapsone
•Other drugs
•Ethionamide
•Ofloxacin, pefloxacin, sparfloxacin (ciprofloxacin is not
active)
•Minocycline and clarithromycin

229

Treatment of leprosy
•Pauci-bacillary: five or less skin lesions (6 months)
•Rifampin 600mg once monthly supervised
•Dapsone 100mg QD
•Multi- bacillary (2 years): more than five skin lesions or
smear positive cases even the lesions are less than five.
•Rifampicin (600mg) once monthly supervised
•Clofazimine 300 mg once monthly supervised
•Dapsone 100 mg OD Clofazimine 50 mg OD

230

Antiviral drugs
231

Overview
•Viruses are obligate intracellular parasites.
•They lack both a cell wall and a cell membrane.
•They do not carry out metabolic processes.
•They use much of the metabolic machinery of the host.
•Few drugs are selective enough to prevent viral replication
without injury to the infected host cells.
232

Overview…
•Clinical symptoms appear late in the course of the disease,
at a time when most of the virus particles have replicated.
•At this stage, administration of drugs that block viral
replication has limited effectiveness in many cases.
•However, a few virus groups respond to available antiviral
drugs, & some drugs are useful as prophylactic agents.
233

Treatment of HIV
234

Class of drugs
Nucleoside/-tide reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
Protease inhibitors (PIs)
Entry inhibitors
Integrase inhibitors
Pharmacokinetic enhancers/“boosters”
235

Sites of action
236

Entry Inhibitors
Enfuvirtide (fusion inhibitor)
•a polypeptide that binds to gp41, preventing the conformational
change.
•Injected subcutaneously twice daily
•Not active against HIV-2
•Treatment-experienced HIV-infected adults & children > 6 years
•Reserved for those with no other treatment options
•Injection site reactions & SC nodules are common

237

Entry Inhibitors…
Maraviroc (CCR5 antagonist)
•blocks the CCR5 co-receptor that works with gp41 to facilitate
HIV entry through the membrane into the cell.
•Treatment-naïve or -experienced HIV-infected adults who have
evidence of predominantly CCR5-tropic virus.
•CYP3A4 substrate susceptible to drug interactions with other
anti-retrovirals.
•Adverse effect: dose- and concentration-dependent orthostatic
hypotension, severe hepatotoxicity.
238

NRTIs
Zidovudine
Lamivudine
Emtricitabine
Tenofovir
Didanosine
Stavudine
Abacavir

•NRTIs are analogs of native ribosides (nucleosides or
nucleotides containing ribose), all lack a 3′-OH group.
•Once they enter cells, they are phosphorylated by
cellular enzymes to the corresponding triphosphate
analog, which is preferentially incorporated into the viral
DNA by RT.
•Because the 3′-hydroxyl group is not present, a 3′,5′-
phosphodiester bond between an incoming nucleoside
triphosphate and the growing DNA chain cannot be
formed, and DNA chain elongation is terminated.
239

Intracellular activation of NRTIs
240 Carbovir 5′-triphosphate

NRTIs…
-NRTIs must first undergo intracellular phosphorylation to
be active.
-All of the NRTIs are administered orally.
-Zidovudine is also available as an iv formulation.
-Tenofovir in 2 different salt forms: Tenofovir Disoproxil
Fumarate (TDF) & Tenofovir Alafenamide (TAF).
-converted by lymphoid cellular enzymes to tenofovir
diphosphate, which is the active form of the drug.
241

NRTIs…
•TAF achieves improved activity at lower doses than TDF.
•Thus, TAF has fewer adverse effects (renal insufficiency and
loss of bone mineral density) than TDF.
•The NRTIs are primarily renally excreted, and all require
dosage adjustment in renal insufficiency except abacavir,
which is metabolized by alcohol dehydrogenase and
glucuronyl transferase.
242

ADRs
•Many toxicities are due to inhibition of the mitochondrial
DNA polymerase in certain tissues.
•The dideoxynucleosides, such as didanosine and stavudine,
have a greater affinity for the mitochondrial DNA
polymerase, leading to toxicities such as peripheral
neuropathy, pancreatitis, and lipoatrophy.
•Because of these mitochondrial toxicities, didanosine &
stavudine are rarely used in current antiretroviral regimens.
243

ADRs…
•All NRTIs potentially cause fatal liver toxicity characterized by
lactic acidosis & hepatomegaly with steatosis (fatty liver).
•Abacavir
•is associated with a hypersensitivity reaction (5%)
•Sensitized individuals should never be re-challenged because of rapidly appearing, severe reactions
that may lead to death.
•A genetic test (HLA-B*5701) is available to screen patients for the potential of this reaction.
244

Resistance
•The most common resistance pattern is a mutation at viral
RT codon 184
•confers a high degree of resistance to lamivudine and
emtricitabine.
•but, restores sensitivity to zidovudine and tenofovir.
•concomitant use of agents with the same analog target is
contraindicated.
•zidovudine and stavudine are both analogs of thymidine and
should not be used together.
245

NRTIs…
NRTIs Comments
Zidovudine
(AZT)

•Do not use with stavudine
•Prevent mother-to-child transmission
•Toxicity: bone marrow supression (anemia, neutropenia),muscle
toxicity (myopathy); inhibits mitochondrial DNA polymerase γ.
Stavudine
(d4T)
•Toxicity: sensory neuropathy and lipoatrophy
•Avoid use, long-term and potentially irreversible toxicities.
Lamivudine
(3TC)
•HIV in adults and children ≥ 3 months
•Chronic hepatitis B (adults, children)
•Essentially nontoxic
Abacavir
(ABC)
•Not active against HBV
•Bioavailability not affected by food
•Toxicity: hypersensitivity syndrome (fever, abdominal pain, rash),
associated with HLA B*5701 genotype
•discontinue drug immediately and never use again as this is
potentially fatal, risk of MI.
246

NRTIs…
NRTIs Comments
Tenofovir(5′-
AMP
derivative)
(TDF or TAF)
•HIV infection (adults, children > 2 years, in combination with
other anti-retrovirals)
•Chronic hepatitis B (adults, children > 12 years)
•HIV pre-exposure prophylaxis (with emtricitabine) in adults at
high risk of infection.
•Toxicity: Nephrotoxicty: small decreases in estimated
creatinine clearance are common; Fanconi syndrome rare;
•decreases in bone mineral density with chronic use.
Emtricitabine
(FTC)
•Chronic hepatitis B (adults, children)
•Generally nontoxic
Didanosine
(DDI)
•Toxicity: sensory neuropathy and pancreatitis
•Avoid use because of long-term and potentially irreversible
toxicities.
247

NNRTIs
•They do not require activation by cellular enzymes.
•HIV-1 specific and not active against HIV-2
•are highly selective, noncompetitive inhibitors of RT.
•Bind to an allosteric hydrophobic site adjacent to the
active site, inducing a conformational change that results
in enzyme inhibition.
•have common characteristics (cross resistance with other
NNRTIs, drug interactions, and a high incidence of
hypersensitivity reactions, including rash).
248

NNRTIs…
NRTIs Comments
Nevirapine
(NVP)
•Autoinducer of its metabolism
•produces rash that usually resolves with continued treatment
•Can rarely produce life-threatening skin eruptions such as
Stevens-Johnson syndrome.
•Rarely produces life-threatening hepatitis.
•Single-dose prevention of mother-to-child transmission
Efavirenz
(EFV)
•commonly causes CNS toxicity that usually resolves with
continued treatment but can be severe.
•Moderate hepatic enzyme inducer
•HIV-1 infection in children ≥ 3 years and adults
•Safe for TB co infected pts
Rilpivirine
(RPV)
•Must be given with food
•Avoid proton pump inhibitors because of reduced absorption
•May cause prolonged QTc interval (if too high conc.)
•HIV-1 infection in children > 12 years and adults
249

NNRTIs…
NRTIs Comments
Etravirine
(ETV)
•Commonly produces rash that usually resolves with continued
treatment.
•Can rarely produce life-threatening skin eruptions such as
Stevens-Johnson syndrome
•Moderate inducer of hepatic enzymes
•Treatment-experienced adults and children ≥ 6 years
•Is a second generation NNRTI active against many HIV strains that
are resistant to the first-generation NNRTIs
•Its use is limited to HIV treatment–experienced, multidrug-
resistant patients who have evidence of ongoing viral replication.
Delavirdine
(DLV)
•Rash commonly and rarely Stevens-Johnson syndrome
•Rarely used because of the requirement for thrice-daily dosing
250

Integrase Inhibitors (INSTI)
•These agents work by inhibiting the insertion of proviral
DNA into the host cell genome.
•The active site of the integrase enzyme binds to the host
cell DNA and includes two divalent metal cations that serve
as chelation targets for the INSTIs.
•As a result, when an INSTI is present, the active site of the
enzyme is occupied and the integration process is halted.
251

Integrase Inhibitors (INSTI)…
•Generally well tolerated (with nausea and diarrhea).
•subject to chelation interactions with antacids, resulting in
significant reductions in bioavailability.
•Resistance to INSTIs occurs with single-point mutations
within the integrase gene.
•Cross-resistance between raltegravir and elvitegravir can
occur, although dolutegravir has limited cross-resistance to
other INSTIs.
252

Integrase inhibitors (INSTI)
Drugs Comments
Raltegravir
(RAL)
•Given twice daily without the need for a PK boosting agent
•Generally well tolerated
•HIV-infected adults and children > 4 weeks of age
Dolutegravir
(DTG)
•Given once daily without the need for a PK-boosting agent
•Generally well tolerated; neural tube risk during 1
st
trimester
•HIV-infected adults and children > 12 years of age
Elvitegravir •Requires cobicistat as a PK booster
•The half-life of Elvitegravir is 3 hours when administered alone,
but increases to approximately 9 hours when boosted by
cobicistat.
•Should be taken with food
•Generally well tolerated
•HIV-infected adults and children > 12 years of age
253

Protease Inhibitors
•are reversible inhibitors of the HIV aspartyl protease
(retropepsin).
•responsible for cleavage of the viral polyprotein into a
number of essential enzymes (RT, protease, and integrase)
and several structural proteins.
•prevents maturation of the viral particles and results in the
production of non-infectious virions.
254

Protease Inhibitors…
•high-fat meals substantially increase the bioavailability of some
PIs, such as nelfinavir and saquinavir, whereas the bioavailability
of indinavir is decreased, and others are essentially unaffected.
•all substantially bound to plasma proteins.
•are substrates for the CYP3A4 isoenzyme
•metabolism is extensive, and very little drug is excreted
unchanged in urine.
•high genetic barrier to resistance, recommended.

255

ADRs
•PIs commonly cause nausea, vomiting, and diarrhea.
•Disturbances in glucose and lipid metabolism also occur,
including diabetes, hypertriglyceridemia, and
hypercholesterolemia.
•Chronic administration results in fat redistribution, including
loss of fat from the extremities, fat accumulation in the
abdomen and the base of the neck (“buffalo hump”) & breast
enlargement.
256

Drug interactions
•are potent inhibitors of CYP450 isoenzymes.
•potentially dangerous interactions with PIs include
•rhabdomyolysis from simvastatin or lovastatin
•excessive sedation from midazolam or triazolam
•respiratory depression from fentanyl
•Others: warfarin, sildenafil, and phenytoin.
•inducers like rifampin are contraindicated with PIs
257

Protease inhibitors
NRTIs Comments
Atazanavir
(ATV)
•usually combined with ritonavir or cobicistat
•can be given without a PK booster at a higher dose of 400 mg
•requires an acidic environment for absorption.
•absorption  with proton pump inhibitors and H2 blockers
•commonly causes unconjugated hyperbilirubinemia
•can cause nephrolithiasis and cholelithiasis
•exhibits a decreased risk of hyperlipidemia compared with other
PIs.
Darunavir
(DRV)
•must be combined with ritonavir or cobicistat
•may cause transient rash & better tolerated than other PIs
•treatment-naïve or -experienced HIV-infected adults and children
> 3 years.
•must be taken with food to increase absorption like atazanavir.
Saquinavir
(SQV)
•second-line treatment of HIV in adults and children
•Rarely used because of better-tolerated alternative PIs
258

Protease Inhibitors…
NRTIs Comments
Ritonavir
(RTV)
•only as a PK-boosting agent in combination with other PIs
•commonly causes nausea
•Associated with elevated cholesterol and triglycerides at
higher doses
•Potent inhibitor of CYP3A4
Fosamprenavir
(FPV)
•Adverse effects: diarrhea, nausea, and vomiting; occasional
skin rashes
•HIV-infected adults, treatment-naïve children ≥ 2 years and
treatment-experienced children ≥ 6 years
Lopinavir
(LPV)
•must be combined with ritonavir
•commonly causes nausea and other GI toxicities
•associated with elevated cholesterol and triglycerides in
adults with prolonged use
•Treatment-naïve or -experienced HIV-infected adults and
children ≥ 14 days.
259

Protease Inhibitors…
NRTIs Comments
Indinavir
(IDV)
•must be taken with ritonavir or while fasting
•Adverse effects: Crystalluria and nephrolithiasis
•Rarely used because of the availability of better-tolerated PIs
•Treatment-naïve or -experienced infected adults & children
Nelfinavir
(NFV)
•The only PI that does not benefit from PK boosting
•Must be taken with food
•Adverse effects: diarrhea and other GI toxicity
•Rarely used because of the availability of better-tolerated PIs
•Treatment-naïve or -experienced infected adults and children
Tipranavir
(TPV)
•Rare but potentially fatal hepatotoxicity; rare but potentially fatal
bleeding diathesis, including intracranial hemorrhage
•Rarely used because of the availability of better-tolerated PIs
•Treatment-experienced HIV-infected adults and children ≥2 years,
generally those who have failed all other PIs
•The only non peptidic protease inhibitor
260

Pharmacokinetic enhancers
Drugs Comments
Ritonavir •is a potent inhibitor of CYP3A4, and concomitant ritonavir
administration at low doses increases the bioavailability of the
second PI, often allowing for longer dosing intervals.
•The resulting higher Cmin levels of the “boosted” PI also help
to prevent the development of HIV resistance.
•Is also moderate hepatic enzyme inducer
•Commonly causes nausea
•Associated with elevated cholesterol and triglycerides at higher
doses.
Cobicistat •enhance the bioavailability of atazanavir, darunavir, and
elvitegravir.
•inhibits CYP3A4, CYP2D6, and the transporter P-gp (numerous
drug interactions exist).
•may also cause elevations in serum creatinine due to inhibition
of tubular creatinine secretion.
261

262

263

ART-regimens
•Selection of the appropriate combination is based on
1.Avoidance of the use of two agents of the same
nucleoside analog.
2.Avoidance of overlapping toxicities and genotypic and
phenotypic characteristics of the virus.
3.Patient factors, such as disease symptoms and concurrent
illnesses.
4.Impact of drug interactions; and
5.Ease of adherence to the regimen.
264

ART-regimens…
•The goals of therapy are
•to maximally and durably suppress HIV RNA replication.
•to restore and preserve immunologic function.
•to reduce HIV-related morbidity and mortality, and to
improve quality of life.
265

ART-regimens…
•Highly active anti-retroviral therapy (HAART) should be initiated in all
living with HIV, regardless of WHO clinical stage & at any
CD4 cell count.
•TB and HIV: first TB followed by ART as soon as possible
with in 8 weeks of treatment
•1
st
line ART for adults should consist of;
•Two NRTIs + a NNRTI or INSTI or boosted PI
•A pregnancy test prior to the initiation of ART
266

ART regimens
Drugs 1
st
line 2
nd
line
Adults TDF + 3TC (FTC) + EFV
(2 NRTI + 1 NNRTI/INSTI)
2 NRTI + Boosted PI
Adolescents TDF + 3TC (FTC) + EFV
TDF + 3TC (FTC) + DTG
(2 NRTI + 1 NNRTI/INSTI)
2 NRTI + Boosted PI
Children
(3-10)
ABC + 3TC + EFV
(2 NRTI + 1 NNRTI)

2 NRTI + Boosted PI (Or
RAL)
Children
(< 3 yrs)
ABC + 3TC + LPV/r
(2 NRTI + 1 PI/INSTI)

2 NRTI + RAL
Infant Prophylaxis: Z + N for 6 weeks
267

Post exposure prophylaxis
•PEP is taken for a total of 28-days
•Should be given in the shortest time possible (within the
first 1-4 hours of exposure).
•Do not consider PEP beyond 72 hours
•Enhanced adherence counselling is necessary
•NVP should not be used in children above the age of 2
years.
268

PEP…
•A regimen of two ARV drugs is effective, but three drugs are
preferred
•Adults and adolescents: TDF+3TC+ PI (RAL/DRV/ are
alternative to PI)
•Children < 10 years: AZT (ABC) +3TC+LPV/r
269

PHARMACOLOGY OF
ANTIPROTOZOAL DRUGS
1

Protozoa
•are eukaryotic and unicellular organisms
•have metabolic processes closer to those of human host
than prokaryotic bacterial pathogens
•Thus the protozoal diseases are less easily treated than
bacterial infections and antiprotozoal drugs are more toxic
•Most important protozoal diseases are
–Malaria, Leishmaniasis
–Amebiasis, Giardiasis
–Trichomoniasis, Trypanosomiasis

2

Introduction
•Malaria is a protozoan disease caused by the plasmodium genus
•Malaria is caused by four common species of protozoa:
•The plasmodium transmitted to human by the bite of an
infected female anopheles mosquito.

3

LIFE CYCLE
•The life cycle consists of
i.sexual cycle takes place in the female anopheline
mosquito, and
ii.asexual cycle occurs in humans
•bite of an infected female mosquito sporozoites- are
injected and reach the bloodstream.
•Within 30 minutes enter the parenchymal cells of the liver
(pre-erythrocytic stage)  in 10-14 days merozoites are
produced /tissue schizonts

4

LIFE CYCLE ….
•The swollen infected liver cell eventually bursts, discharging
motile merozoites into the bloodstream
•Merozoites bind to and enter the red cells of the blood
(erythrocytic stage) and become trophozoites
•Following mitotic replication of its nucleus, the parasite in the
red cell is called a schizont(blood schizonts), and its rapid
growth and division is called schizogony
•schizogony results in the production of further merozoites
•Merozoites released when RBCs repture

5

LIFE CYCLE ….
•merozoites then bind to and enter fresh red cells and the
erythrocytic cycle starts all over again
•Some merozoites, on entering red cells, differentiate into
male and female forms of the parasite, called
gametocytes.
•In P. vivax and P. ovale infections, a proportion of the
intrahepatic forms do not divide immediately but remain
dormant for a period ranging from 3 weeks to a year or longer
before reproduction begins hypnozoites

6

LIFE CYCLE …
•P. malariae & p. falciparum have one cycle of liver
invasion and end by the 4th week i.e. no relapse occurs.
•P.ovale & p. vivax have dormant stages (hypnozoites) in the
liver. These hypnozoites may rupture months or years later
causing relapse of the attacks.

7

Exo-
erythrocytic
(hepatic) cycle
Hypnozoites
Sporozoites
Mosquito Salivary
Gland
Gametocytes
Oocyst
Erythrocytic
Cycle
Zygote
Life Cycle …
8

Erythrocyte Changes in Malaria
•the growing malarial parasite progressively consumes and
degrades intracellular proteins, principally hemoglobin
•The potentially toxic heme is detoxified by polymerization to
biologically inert hemozoin (ferriprotoporphyrin IX).
•alters the RBC membrane by changing its transport properties,
exposing cryptic surface antigens, and inserting new parasite-
derived proteins
9

Treatment
Actions
– drug acts on early stages in
liver, before release of merozoites into blood
(clinical prophylaxis or cure)–
attack parasite in RBC, preventing or ending clinical attack
– destroy sexual forms in human, decreases
transmission
– kill dormant
hypnozoites in liver, anti relapse drugs
– inhibit development of oocysts in mosquito,
decreases transmission
10

Antimalaria drugs
Fig. Sites of antimalarial drugs 11

4-AMINOQUINOLINES
Chloroquine
•is a very potent blood schizontocidal drug
•does not have any effect on sporozoites, hypnozoites or
gametocytes
•given orally, is completely absorbed, is extensively distributed
throughout the tissues and is concentrated in parasitized red
cells
12

Chloroquine …
Mechanism of action:
•Blocks heme polymerization and causes accumulation of
heme w/c is toxic to the protozoa
•Increases pH of the vacuoles in the parasite, so prevent its
utilization of erythrocyte hemoglobin.

13

Chloroquine …
Resistance
•is now very common among strains of P falciparum
•uncommon but increasing for P vivax (recently detected in
ethiopia).
•In P. falciparum, mutations in a putative transporter, PfCRT,
have been correlated with resistance
•A parasite-encoded efflux mechanism may account for the
reduced levels of chloroquine in the digestive vacuoles of
chloroquine-resistant parasites
14

15

Chloroquine …
Therapeutic Uses
•highly effective against the erythrocytic forms of P. vivax, P.
ovale, P. malariae, P. knowlesi, and chloroquine-sensitive
strains of P. falciparum.

•For infections caused by P. ovale and P. malariae, it remains
the agent of choice for chemoprophylaxis and treatment.
16

Chloroquine …
Uses:
•Acute attack 600 mg base (4 tab.) then 300 mg after 6 h. then 150 mg
bid for two more days.
–(4
+ 2) +2 +2 =for 3 days or 4, 4, 2 150 mg tabs for 3 days
•Add 100 mg proguanil/ day (2 tab.) in chloroquine-resistant area

Chemoprophylaxis:
•150mg base (2 tab.) / week,
•one week before entering the endemic area & 4 weeks after
leaving
Other uses
•Amebic liver abscess (as chloroquine is concentrated in the liver).
•Anti-inflammatory in autoimmune diseases e.g. rheumatoid arthritis
17

Chloroquine …
ADRs
•nausea and vomiting, dizziness and blurring of vision,
headache, and urticarial symptoms.
•Large doses have sometimes resulted in retinopathies

is considered to be safe for use by pregnant women
contraindicated in patients with psoriasis or porphyria
oantidiarrheal agent kaolin and calcium- and magnesium-
containing antacids interfere with the absorption of
chloroquine and should not be coadministered with the
drug

18

• an alkaloid derived from cinchona bark (quinine,
quinidine, mefloquine).
•is a blood schizonticidal drug effective against the
erythrocytic forms of all four species of plasmodium
•no effect on exoerythrocytic forms
•gametocidal against P vivax and P ovale but not P
falciparum
Mechanism of action:
•bind heme and prevent its detoxification
19

•usually given orally in a 7-day course, but it can be given by slow
intravenous infusion for severe P. falciparum infections and in
patients who are vomiting
Uses:
•Chloroquine-resistant P. falciparum (orally).
•Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it could
repeated at an intervals of 8-12 h. until patient can take the drug
orally
•In pregnancy 7-day course of quinine alone should be
given
20

Adverse effects
Causes triads of side effects
•Cinchonism  nausea, dizziness, tinnitus, headache and
blurring of vision.
•Hypoglycemia (quinine stimulates release of insulin from
the pancreas)
•hypotension, cardiac dysrhythmias and severe central
nervous system (CNS) disturbances such as delirium and
coma

21

Mefloquine
•is a blood schizonticidal
•no effect on hepatic forms of the parasites
•given orally and is rapidly absorbed.
•a slow onset of action and a very long plasma half-life (up to
30 days), which may be the result of enterohepatic
cycling or tissue storage
22

Mefloquine …
•50% of subjects complain of gastrointestinal disturbances.
•Transient CNS toxicity-giddiness, confusion, dysphoria and
insomnia
•is contraindicated in pregnant women and in women
liable to become pregnant within 3 months of stopping the
drug
•contraindicated if there is a history of epilepsy,
psychiatric disorders, arrhythmia, cardiac conduction
defects, or sensitivity to related drugs
23

• is a tissue schizonticide (active against hepatic stages of all
human malaria parasites).
•has a cellular
oxidant activity and possibly interferes with
mitochondria function
•is the drug of choice for the eradication of dormant liver
forms of P vivax and P ovale
•is the only available agent active against the dormant
hypnozoite
•gametocidal against the four human malaria species
–inhibits infection transmission 24

•Primaquine may be converted to electrophilic inter-mediates
that act as oxidation-reduction mediators.
•Such activity could contribute to antimalarial effects by generating
reactive oxygen species or by interfering with mitochondrial
electron transport in the parasite
•Standard doses of primaquine may cause hemolysis or
methemoglobinemia (manifested by cyanosis), especially in
persons with G6PD deficiency or other hereditary metabolic
defects
•Should not be given for pregnant women. So how relapse
from p.vivax & ovale can be prevented??????????????
25

HALOFANTRINE & LUMEFANTRINE

Halofantrine hydrochloride
•is effective against erythrocytic stages
•Oral absorption is enhanced with food
•abdominal pain, diarrhea, vomiting, cough, rash,
headache, pruritus, and elevated liver enzymes
•alters cardiac conduction, with dose-related prolongation
of QT and PR intervals
•contraindicated in patients with cardiac conduction
defects and should not be used in those who have
recently taken mefloquine
26

Lumefantrine
•is structurally related to quinine and is effective against P.
falciparum particularly when combined with either
mefloquine or artemisinin derivatives
–Quartem = artemeter + lumefantrine
•oral absorption is highly variable and improved when the
drug is taken with food

27

Coartem dosing for pediatrics

28

ARTEMISININ AND RELATED COMPOUNDS
Artemisinin
•is poorly soluble in water and a fast-acting blood
schizonticide effective in treating the acute attack of
malaria (including chloroquine-resistant and cerebral malaria).
•Artesunate, a water-soluble derivative, and the synthetic
analogues
•Artemether and artether lipid soluble
29

Artemisinin …
•converted in the liver to the active metabolite
dihydroartemisinin
•do not have any effect on liver hypnozoites and are not useful
for chemoprophylaxis
•very rapidly acting blood schizonticides against all
human malaria parasites
•Recrudescence rates are unacceptably high after short-
course therapy
30

Artemisinin …
Mechanism of action
•Formation of potentially toxic heme-adducts
•Generate free radicals that alkylate and oxidize proteins and
possibly lipids in parasitized erythrocytes
31

Artemisinin …
Resistance
•Artemisinins do not display significant clinical cross resistance
with other drugs
•Recent evidence has nonetheless suggested the emergence of
P. falciparum isolates with an increased tolerance to
artemisinins, manifesting as longer parasite clearance times
•WHO recommend Artemisinin Combination Therapy (ACTs)
to
–Increase treatment efficacy and
–Prevent the emergence of drug resistance.
32

Artemisinin …
Pharmacokinetics
•The semisynthetic artemisinins have been formulated for
Oral (dihydroartemisinin, artesunate, & artemether), IM
(artesunate & artemether), IV(artesunate), & rectal (artesunate)
routes.
•Bioavailability after oral dosing typically is ≤30%
•Both artesunate and artemether
have modest levels of plasma protein binding (43 -82%).
are extensively metabolized and converted to dihydroartemisinin,
which has aplasma t
1/2 of 1-2 hours

33

Artemisinin …
Therapeutic Uses
•Due to their rapid and potent activity against even MDR
parasites, the artemisinins are valuable for the treatment of
severe P. falciparum malaria.
•Intravenous artesunate is more than comparable to a
standard quinine regimen, likely possessing higher efficacy and
a better safety profile in many patient populations
•Artemisinins should not be used for chemoprophylaxis
because of their short t
1/2, which translates into high
recrudescence rates.

34

Artemisinin …
•The artemisinins generally are not used alone because of their
limited ability to eradicate infection completely (short plasma t
1/2)

•Combining an artemisinin derivative with a
longer lasting partner
drug assures sustained antimalarial activity.

•Current ACT regimens that are well tolerated in adults and
children ≥5 kg include artemether-lumefantrine, artesunate-
mefloquine, artesunate-amodiaquine, artesunate-
sulfoxadine-pyrimethamine, and dihydroartemisinin-
piperaquine.

35

Artemisinin …
Toxicity and Contraindications
•Potential toxic effects in infants and during the first trimester
of pregnancy.
•ACTs not be used for the treatment of children ≤5 kg or
during the first trimester of pregnancy
36

ANTIBIOTICS

•Tetracycline and doxycycline are active against
erythrocytic schizonts of all human malaria parasites.
•They are not active against liver stages.
•Doxycycline is commonly used in the treatment of
falciparum malaria in conjunction with quinidine or
quinine, allowing a shorter and better-tolerated course
of quinine.
• Doxycycline has also become a standard
chemoprophylactic drug
37

ANTIBIOTICS …
•Clindamycin is slowly active against erythrocytic
schizonts and can be used in conjunction with quinine
or quinidine in those for whom doxycycline is not
recommended, such as children and pregnant women.
38

INHIBITORS OF FOLATE SYNTHESIS
•Pyrimethamine
•Proguanil
•Sulfadoxine
ATOVAQUONE (interferes with cytochrome electron transport)
, a fixed combination of atovaquone (250 mg)
and proguanil (100 mg), is highly effective for both the
treatment and chemoprophylaxis of falciparum malaria

39

Chemoprophylaxis of malaria
•Chloroquine 150 mg base ( 2 tab/week)
•Chloroquine ( 2 tab/week) plus proguanil 100 mg (one or
two tab/ day) or
•Mefloquine 250 mg (one tab./ week)

41

Drugs used in amebiasis
42

amebiasis
is infection by the protozoan parasite Entamoeba histolytica.
E histolytica infection may present as a severe intestinal infection
(dysentery), a mild to moderate symptomatic intestinal infection,
an asymptomatic intestinal infection, ameboma, liver abscess, or
other type of extraintestinal infection.
 The choice of drug depends on the clinical presentation and on
the desired site of drug action, ie, in the intestinal lumen or in the
tissues.
43

•Ameba has two stages of development:
Cyst and
Trophozoite
cysts (colon) —— asymptomatic intestinal infection, source of infection
big trophozoites (tissues of intestine) —— intestinal amebiasis
→ extraintestinal infection

Classification of antiamoebic drugs
Based on clinical use
•Tissue amebicides
eliminate organisms primarily in the bowel wall, liver, and
other extraintestinal tissues and are not effective against
organisms in the bowel lumen.

Include chloroquine, emetine & dihydroemetine

45

Classification …
•Luminal amebicides
–act primarily in the bowel lumen
Diloxanide furoate
Iodo-quinol
Tetracyclines, paromomycin and erythromycin

•Mixed amebicides
–Act both on intestinal & extra intestinal Amebiasis
•Metronidazole
•tinidazole
46

Antiamoebic drugs
Metronidazole
Pharmacokinetics:
Oral Metronidazole is readily absorbed and permeates all
tissues including cerebrospinal fluid, breast milk, alveolar
bone, liver abscesses, vaginal secretions, and seminal fluid.
Intracellular concentrations rapidly approach extracellular
levels whether administered orally or intravenously.
Protein binding is low.
The drug and its metabolites are excreted mainly in the
urine.
47

Mechanism of Action
•The nitro group of metronidazole is chemically reduced by
ferredoxin within sensitive organisms.
•The reduction products appear to be responsible for killing the
organisms by reacting with various intracellular macromolecules.
Clinical Uses:
•Metronidazole is active against amebiasis, urogenital
trichomoniasis, giardiasis, anaerobic infections, acute ulcerative
gingivitis, and bacterial vaginitis and Helicobacter pylori infection
48

Adverse effects
•Nausea, headache, dry mouth, or metallic tastes
occur commonly.
•Rare adverse effects include vomiting, diarrhea,
insomnia, weakness, dizziness, stomatitis, rash, urethral
burning, vertigo, and paresthesias.
•It has a disulfiram-like effect.

49

Other Nitroimidazoles
•Other nitroimidazole derivatives include tinidazole, and
ornidazole
•They have similar adverse effects
•Because of its short half-life, metronidazole must be administered
every 8 hours; the other drugs can be administered at longer
intervals
•However, with the exception of tinidazole, the other
nitroimidazoles have produced poorer results than
metronidazole in the treatment of amebiasis.
50

Chloroquine
Chloroquine reaches high liver concentrations and is highly
effective when given with emetine in the treatment and
prevention of amebic liver abscess.
Chloroquine is not active against luminal organisms.
51

Dehydroemetine & Emetine
•Emetine and dehydroemetine are administered parenterally.
They are stored primarily in the liver, lungs, spleen, and kidneys.
•They are eliminated slowly via the kidneys.
•These drugs act only against trophozoites, which they directly
eliminate.
Clinical Uses:
•Severe Intestinal Disease (Amebic Dysentery): Parenterally
administered emetine and dehydroemetine rapidly alleviate
severe intestinal symptoms
52

Mechanisms

Inhibiting peptidyl-tRNA transposition → inhibiting elongation
of peptide chain → inhibiting protein synthesis → interfering
cleavage and breeding of trophozoites
Adverse Effects:
•Sterile abscesses, pain, tenderness, and muscle weakness in the
area of the injection are frequent.
•Emetine and dehydroemetine should not be used in patients with
cardiac or renal disease, in patients with a history of polyneuritis,
or in young children or liver abscess.
•They should not be used during pregnancy.

53

Diloxanide Furoate
•Diloxanide furoate is directly amebicidal, but its mechanism of action
is not known.
•In the gut, diloxanide furoate is split into diloxanide and furoic acid;
about 90% of the diloxanide is rapidly absorbed and then conjugated
to form the glucuronide, which is rapidly excreted in the urine.
•The unabsorbed diloxanide is the active antiamebic substance.
•Diloxanide furoate is the drug of choice for asymptomatic infections.
•For mild intestinal disease, and other forms of amebiasis it is used
with another drug.
54

Iodoquinol
•Iodoquinol is effective against organisms in the bowel lumen but
not against trophozoites in the intestinal wall or extraintestinal
tissues.
•The mechanism of action of iodoquinol against trophozoites is
unknown.
•Iodoquinol is an alternative drug for the treatment of
asymptomatic or mild to moderate intestinal amebiasis.
Adverse Effects:
•Reversible severe neurotoxicity (optic atrophy, visual loss, and
peripheral neuropathy).
55

Paromomycin Sulfate
•Aminoglycoside antibiotic.
•Not significantly absorbed from the gastrointestinal tract.
•Paromomycin is an alternative drug for the treatment of asymptomatic
amebiasis. In mild to moderate intestinal disease, it is an alternative
luminal drug used concurrently with metronidazole.
•Paromomycin is both directly and indirectly amebicidal; the indirect
effect is caused by its inhibition of bowel bacteria.
•It can be used only as a luminal amebicide and has no effect in
extraintestinal amebic infections
56

Drugs used in Giardiasis and Trichomoniasis
•Metronidazole is a drug of choice for gardiasis and
trichomoniasis, and the alternate drug is tinidazole.
57

Treatment of Leishmaniasis
Kala-azar, cutaneous, and mucocutaneous leishmaniasis
are caused by the genus Leishmania
Treatment of leishmaniasis is difficult because of drug
toxicity, the long courses of treatment, treatment failures,
and the frequent need for hospitalization
The drug of choice is sodium antimony gluconate
(sodium stibogluconate).
Alternative drugs are amphotericin B and pentamidine.
Amphotericin B is injected slowly intravenously. Patients
58

The Pharmacology of
antihelminthics
59

Helminths
•Infection by helminths (worms) may be limited solely to the
intestinal lumen or may involve a complex process with
migration of the adult or immature worm through the body before
localization in a particular tissue

•Pathogenic helminths can be divided in to : cestodes (flatworms),
nematodes (roundworms), trematodes (flukes) and less frequently,
Acanthocephala (thorny-headed worms).
60

Helminths …
•Nematodes are long, cylindrical unsegmented worms that are
tapered at both ends. Because of their shape,
They are commonly referred to as roundworms
Some of the nematodes (filarial worms and guinea worms) live
in blood, lymphatics, and other tissues and are referred to as
blood and tissue nematodes
Others are found primarily in the intestinal tract
Hookworms, Strongyloides stercoralis
Pinworms, Ascaris spp
61

Helminths …
•Cestodes, or tapeworms, are flattened dorsoventrally and are
segmented.
•The tapeworm has a head with round suckers or sucking grooves.
•Some tapeworms have a projection (rostellum) that bears hooks.
•This head, or scolex (also referred to as the hold-fast organ), is
used by the worm to attach to tissues
•Trematodes (flukes) are nonsegmented flattened helminths that
are often leaflike in shape.
•Most have two suckers, one found around the mouth (oral sucker)
and the other on the ventral surface.
62

Antihelmenthics
Benzimidazoles (BZ): Thiabendazole, Mebendazole & Albendazole
Mechanism of Action.
•inhibition of microtubule polymerization by binding to β-
tubulin.
•higher affinity for parasite β-tubulin than for the same target in higher
eukaryotes.
•In nematodes
–inhibition of mitochondrial fumarate reductase,
–reduced glucose transport, and
–uncoupling of oxidative phosphorylation,
63

Benzimidazoles
–broad spectrum anthelminthic
•MOA:
–Mebendazole binds to both mammalian & nematode tubulins
but with higher affinity for the later (explains its selective
action)
–This selective binding to nematode tubulin inhibits glucose
absorption
•Leading to glycogen consumption & ATP depletion
64

Pharmacokinetics
•Is administered orally & poorly absorbed from GIT
•Most of the drug is excreted in the faces with in 24 hours of
administration
•less than 10% of orally administered drug is absorbed
•Absorption increases with fatty meal
•Absorbed drug is 90% protein bound
• Converted to inactive metabolites & excreted in urine mostly
•Has t1/2 of 2-6 hours

65

Therapeutic use
•Is primarily used for treatment of
–A. lumbricoids, T. trichiuria
–E. vermicularis & Hook worm infections
•It is taken orally before or after meal, tablets should be
chewed before swallowing
•Due to its broad spectrum activity, it is used for mixed
infections
•In adults and children over 2 years, cure rate is 90-100 %
except hookworm w/ch is less

66

Side effects & precautions
•Short term therapy: Mild GI disturbance
• High dose: hypersensitivity reactions, agranulocytosis,
alopecia, elevation of liver enzymes
•Used with caution under 2 years of age, b/s it may cause
convulsions
•Contraindicated in pregnancy
67

Albendazole
Mechanism of Action:
•it causes micro tubular degeneration which in turn
impairs vital cellular processes & leads to parasite death
•It also inhibits helminth specific ATP generation by
furamate reductase
•has larvicidal effects in hydatid disease, cysticercosis,
ascariasis, and hookworm infection and ovicidal effects in
ascariasis, ancylostomiasis, and trichuriasis.

68

Albendazole
Pharmacokinetics
•Is administered orally & has poor absorption
•Oral bioavailability is increased 5 times when it is administered with
fatty foods than empty stomach
• Metabolized in the liver to the active metabolite albendazole
sulfoxide
•Plasma half life is 8-12 hours & metabolites are excreted in urine
•Used on empty stomach when used against intraluminal
parasites but with a
fatty meal when used against tissue
parasites

69

Albendazole ….
•is a broad spectrum drug which has activity against:
•Nematodes, Cestodes, Liver flukes
•Giardia lumblia, Ascariasis
•Pinworms, hook worms
•Strongyloidiasis, Hydatid cyst disease (echinococcosis)
•It is effective in treating cerebral & spinal
neurocysticercosis
it is also used with corticosteroid to decrease the
inflammation caused by dying organism and it also
reduces the duration of course for 21 days

70

Albendazole ….
•Side effects:
– In short term(1-3 days): Mild epigastric pain, diarrhea, nausea,
headache & insomnia
– In long term use : for hydatid cyst and cysticercosis:
abdominal pain, headache, fever, fatigue, alopecia, increased
liver enzymes, pancytopenia
•C/I:
–Not given during pregnancy, hypersensitive people to
benzimidazole drugs & children under 2 years

71

Piperazine
•is an orally given drug used for treatment of Ascaris lumbricoids and
Enterobios vermicularis (pin worm)
•Readily absorbed from GIT & most of the drug is excreted from the
body with in 24 hours
MOA:
–Piperazine acts as an agonist at parasite specific Cl- channels
on the parasite muscle
–This causes Cl- dependent hyperpolarization of the muscle
membrane & flaccid paralysis
–This paralysis results in expulsion of the worms
•Now days it is replaced by mebendazole
72

Piperazine ….
Side effects
•GI distress, urticaria, dizziness
•Neurological symptoms such as ataxia, hypotonia, visual disturbances &
exacerbation of epilepsy can occur with preexisting renal insufficiency
Contraindications
•pregnant women due to formation of potentially carcinogenic &
teratogenic
nitrosamine metabolites
•Epilepsy or a history of epilepsy
• Impaired liver or kidney functions, chronic neurologic disease

73

Pyrantel pamoate
MOA:
•Depolarizing neuromuscular blocking agent.
•it opens nonselective cation channels and induce persistent
activation of nicotinic acetylcholine receptors and spastic
paralysis of the worm
•Its selective toxicity occurs as the neuromuscular junction of the
helminths is more sensitive to the drug than is the mammalian
muscle
•Pyrantel also inhibits cholinesterases
74

Pyrantel pamoate ….
Pharmacokinetics
•It is poorly absorbed from the GI tract, a property that confines
its action to intralumenal GI nematodes.
•Less than 15% is excreted in the urine as parent drug and
metabolites.The major proportion is recovered in the feces
Therapeutic Uses.
•It is an alternative to mebendazole or albendazole in the
treatment of ascariasis and enterobiasis.
•High cure rates have been achieved after a single oral dose of 11
mg/kg, to a maximum of 1 g.
•It is also effective against hookworm infections caused by
Ancylostoma duodenale and Necator americanus, although
repeated doses are needed to cure heavy infections by N.
americanus
75

Pyrantel pamoate ….
Contraindication
•pregnant mother & children under the age of 2 year is not
recommended
Side effects :
–Headache, Dizziness, Drowsiness
Drug interaction
•pyrantel pamoate and piperazine are mutually antagonistic
with respect to their neuromuscular effects on parasites,
they should not be used together.
76

•Is a drug used extensively in the treatment of tape worm
infections caused by:
–Taenia saginata (beef tapeworm)
–Taenia solium (pork tapeworm)
–Diphyllobothrium latum (fish tapeworm)
–Hymenolepis nana
–Other tapeworm infections
•MOA:
–Niclosamide inhibits production of energy by inhibiting
oxidative phosphorylation in the parasite

77

…..
•The drug affects the scolex & proximal segments of the cestodes
–Resulting in detachment of the scolex from intestinal wall
& evacuation of cestodes from the intestine by normal
peristaltic actions of the host bowl
–It can also uncouple oxidative phosphorylation in
mammalian mitochondria
»But this requires doses higher than those commonly
used in treating worms
–A single dose is adequate to produce a cure rate of 95%
–With Hymenolepis nana (dwarf tapeworm) a longer treatment
course (up to 7 days) is necessary
78

…..
•The adult dose of niclosamide is 2 g once, given in the morning on an
empty stomach.
•The tablets must be chewed thoroughly and then swallowed with water.
•Side effects:
–Mild ,infrequent and transitory GI disturbance
–Loose stools
•Contraindications
– Alcohol consumption should be avoided
– Not indicated in children under 2 years of age or in pregnancy

79

Praziquantel
•Is a broad spectrum & well tolerated drug
•It is most effective of the drugs used in the treatment of
schistosomiasis
–Have activity against male, female & immature stages of the
parasite
–It is active against all the 3 species of schistosoma
•Schistosoma mansoni, japonicum & hematobium
•MOA: praziquantel increases Ca++ permeability through parasite
specific ion channels & causes muscle cells of the parasite spastic
paralysis
80

Praziquantel …..
•In addition to its efficacy in treating schistosoma, it has also
activity against other flukes such as
–C. sinensis
–Paragonimus westermani
–Tape worms (T. saginata, T. solium, H. nana & D. latum)
•Praziquantel
–Is taken orally & readily absorbed
–It has a t1/2 of about 1.5 hours
–Bioavailability is reduced by Carbamazepine & phenytoin &
increased by Cimetidine
–Excreted in the urine
81

Praziquantel …..
•Side effects
–Occur with in few hours of administration
–Includes:
•Nausea
• vomiting
• abdominal discomfort
82

Oxamniquine
•Is another drug used in the treatment of trematode infections
•But unlike praziquantel, oxamniquine has a restricted range of
efficacy being active against Schistosoma mansoni infections
•MOA:
–Oxamniquine esterify & binds to parasite DNA leading to
the death of schistosome by interruption of its nucleic
acid & protein synthesis
–Selective toxicity arises due to the fact that the fluke esterify
oxamniquine to produce a reactive metabolite that
alkylates parasite DNA
83

Diethylcarbamazine
•Is a drug active against several micro filarial & adult filarial worms
•It is the drug of choice for certain types of filarial infections only,
such as: Wuchereria bancrofti, Brugia malayi & Lao lao
MOA:
•it interferes with metabolism of arachidonic acid & blocks the
production of PGs
Resulting in capillary vasoconstriction & impairment of the
passage of microfilaria
It sensitizes the host immune system & increases Phagocytosis &
killing of the filarial species
84

Diethylcarbamazine …
•Administered orally & well absorbed from GIT
•Peak plasma level obtained with in 4 hours
•The drug disappears from the blood with in 48 hours by
excretion in the urine
–Dosage should be adjusted in patients with renal
insufficiencies
•Caution is necessary when taking this drug
–Particularly when treating onchocerciasis (ivermectin- DOC)
•Sudden death of microfilaria can produce severe reactions
with in hours of drug administration (
Mazotti reaction)
Fever, lymphadenopathy, cutaneous swelling,
leukocytosis, edema, rashes, tachycardia & headache
•Side effects: malaise, headache, arthralgia & GI symptoms
85

Ivermectin
•Is a drug with broad spectrum activity against
•Onchocerciasis & other filarial infections
•Strongyloidiasis, Ascariasis
•Loiasis, Cutaneous larva migrans
MOA:
•Activates parasite specific inhibitory glutamate gated chloride
channels which are physiologically related to vertebrate GABA-gated
Cl- channels
•So it causes hyperpolarization of parasite cell membrane &
paralysis of muscle
–At higher doses it can inhibit GABA-gated Cl- channels
•But it has no paralytic action in mammals b/s Ivermectin doesn’t
adequately cross BBB 86

Ivermectin ….
•Pharmacokinetics
–Is administered by oral & subcutaneous routes
–Is rapidly absorbed & have t1/2 of 12 hours
–Is excreted in faces unchanged
•Side effects
–Are minimal as compared to diethylcarbamazine
–Includes: pruritus, fever, tender lymph nodes
•Contraindications
–Concomitant use with other drugs that enhance GABA
E.g. Barbiturates, benzodiazepines, valporic acid
– pregnancy, meningitis
–Children under 5 years of age

87

The pharmacology 0f
ANTIFUNGAL AGENTS

Fungi
•There are 200,000 known species of fungi, and estimates of
the total size of Kingdom Fungi range to well over a million.
•Fortunately, only ~400 fungi cause disease in animals, and even
fewer cause significant human disease.
•However, fungal infections are becoming more common:
•Patients with AIDS and patients whose immune systems are
compromised by drug therapy are especially susceptible to
mycotic infections.

Fungi ….
•Fungi are eukaryotes with unique cell walls containing
glucans and chitin, and their eradication requires different
strategies than those for treatment of bacterial infections.
•Available agents have effects on the synthesis of membrane
and cell-wall components, on membrane permeability, on the
synthesis of nucleic acids, and on microtubule/mitotic spindle
function

Fungal Infections (Mycoses)
•Diseases caused by fungi include superficial infections of
the skin by dermatophytes

Fungal Infections…
•Systemic infections are caused by the inhalation of spores
and cause fungal pneumonia

Fungal Infections…
•Organisms that cause opportunistic infections will not gain a
foothold in healthy individuals, but in the immuno compromised
they can cause serious, sometimes life-threatening infections.

Antifungal drugs
•The antifungal drugs fall into two groups: antifungal antibiotics and
synthetic antifungals.
Amphotericin B
•is poorly absorbed from the gastrointestinal tract.
•Oral it is effective only on fungi within the lumen of the tract.
•The drug is widely distributed in tissues, but only 2-3% of the blood
level is reached in CSF, thus occasionally necessitating intrathecal
therapy for certain types of fungal meningitis

Mechanism of Action
•Amphotericin B binds to ergosterol (a cell membrane sterol)
and alters the permeability of the cell by forming
amphotericin B-associated pores in the cell membrane.

•The pore allows the leakage of intracellular ions (K
+
) and
macromolecules, eventually leading to cell death.

Antifungal Activity:
•Amphotericin B is a broad-spectrum antifungal agent. It has
activity against yeasts including; Candida albicans and Cryptococcus
neoformans; molds, Aspergillus fumigatus.
Clinical Use:
•Amphotericin B remains the drug of choice for nearly all life-
threatening mycotic infections(systemic infections)
•Used as the initial induction regimen for serious fungal infections
(immunosuppressed patients, severe fungal pneumonia, and
cryptococcal meningitis with altered mental status).

Adverse Effects:
•The toxicity of amphotericin B which may occur immediately
or delayed include fever, chills, muscle spasms, vomiting,
headache, hypotension (related to infusion), renal damage
associated with decreased renal perfusion (a reversible) and
renal tubular injury (irreversible).

•Anaphylaxis, liver damage, anemia occurs infrequently.

Nystatin
•It has similar structure with amphotericin B and has the same
mechanism of action.
•It is too toxic for systemic use and is only used topically.
•It is not absorbed from skin, mucous membranes, or the
gastrointestinal tract.
•Nystatin is active against most Candida species and is most
commonly used for suppression of local candidal infections.
•Nystatin is used in the treatment of oropharyngeal thrush, vaginal
candidiasis, and intertriginous candidal infections.

Griseofulvin
•Griseofulvin is a fungistatic and used is in the treatment of
dermatophytosis.
Mechanism of Action
•Griseofulvin inhibits microtubule function and thereby disrupts
assembly of the mitotic spindle.
•Thus, a prominent morphological manifestation of the action of
griseofulvin is the production of multinucleate cells as the drug
inhibits fungal mitosis.
•In addition to its binding to tubulin, griseofulvin interacts with
microtubule-associated protein

Griseofulvin ….
•Absorption is improved when it is given with fatty foods.
•Griseofulvin is deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection.
• It must be administered for 2-6 weeks for skin and hair infections
to allow the replacement of infected keratin by the resistant
structures.
•Nail infections may require therapy for months to allow regrowth
of the new protected nail and is often followed by relapse
•Systemic administration for local effect

Flucytosine
•Flucytosine is related to fluorouracil (5-FU).
•Flucytosine is converted intracellularly first to 5-FU and then to 5-
fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and RNA synthesis,
respectively.
•Its spectrum of action is much narrower than that of amphotericin
B

Flucytosine: mechanism of action
The selective action of flucytosine is due to the lack of cytosine
deaminase in mammalian cells, which prevents metabolism to
fluorouracil

Flucytosine
Clinical Use
•Active against Cryptococcus neoformans, some Candida species,
and the dematiaceous molds that cause
chromoblastomycosis.
•Clinical use at present is confined to combination
therapy, either with amphotericin B for cryptococcal
meningitis or with itraconazole for chromoblastomycosis

Adverse Effects:
•The adverse effects of flucytosine result from metabolism
(intestinal flora) to the toxic antineoplastic compound 5-
fluorouracil.

•Bone marrow toxicity with anemia, leukopenia, and
thrombocytopenia are the most common adverse effects,

Azoles
•are synthetic compounds that can be classified as
Imidazoles
•clotrimazole, miconazole, ketoconazole, econazole,
•butoconazole, oxiconazole, sertaconazole, sulconazole
Triazoles
•terconazole, itraconazole, fluconazole,
•voriconazole, posaconazole, isavuconazole

Azoles …..
Mechanism of Action
•Reduce ergosterol synthesis by inhibition of fungal cytochrome
P450 enzymes and lead to the accumulation of 14-α-methylsterols.
•These methylsterols may disrupt the close packing of acyl chains of
phospholipids, impairing the functions of certain membrane-bound
enzyme systems, thus inhibiting growth of the fungi.
•Some azoles directly increase permeability of the fungal
cytoplasmic membrane

Azoles …..
•The specificity of azole drugs results from their greater affinity for
fungal than for human cytochrome P450 enzymes.

•Imidazoles exhibit a lesser degree of specificity than the triazoles,
accounting for their higher incidence of drug interactions and side
effects.

Azoles: antifungal activity
•Azoles are active against many Candida species, Cryptococcus
neoformans, the endemic mycoses (blastomycosis,
coccidioidomycosis), the dermatophytes, and, Aspergillus infections
(itraconazole).
Adverse Effects:
•The azoles are relatively nontoxic.
•The most common adverse reaction is minor GIT upset.
•Most azoles cause abnormalities in liver enzymes and, very rarely,
clinical hepatitis

Interaction of Azole Anti-Fungals with Other Drugs
•The azoles interact with hepatic CYPs as substrates and inhibitors,
providing myriad possibilities for the interaction of azoles with many
other medications.
•azoles can elevate plasma levels of some co-administered drugs.
•Other co-administered drugs can decrease plasma concentrations of
azole antifungal agents.
•As a consequence of myriad interactions, combinations of certain
drugs with azole antifungal medications may be contraindicated

Ketoconazole
•is less selective for fungal P450 than fluconazole and itraconazole
Clinical use:
•it has limited use because of the drug interactions, endocrine side
effects, and of its narrow therapeutic range.
•Oral formulation that is best absorbed at a low gastric pH.
•Ketoconazole is used in treatment of mucocutaneous candidiasis
and nonmeningeal coccidioidomycosis.
•It is also used in the treatment of seborrheic dermatitis and
pityriasis versicolor (Topical/ shampoo).

Adverse effects
•ketoconazole inhibition of human CYP450 enzymes
interferes with biosynthesis of adrenal and gonadal steroid
hormones, producing significant endocrine effects such as
gynecomastia, infertility, and menstrual irregularities
can alter the metabolism of other drugs, leading to enhance
toxicity of those agents

Clotrimazole and miconazole
•Clotrimazole and miconazole are available over-the-counter and
are often used for vulvovaginal candidiasis.
•Oral clotrimazole troches are available for treatment of oral
thrush and are a pleasant-tasting alternative to nystatin
•In cream form, both agents are useful for dermatophytic
infections, including tinea corporis, tinea pedis, and tinea cruris.
•Absorption is negligible, and adverse effects are rare.

Fluconazole
•Fluconazole has good cerebrospinal fluid penetration.
•Can be given by the intravenous or the oral route.
•Fluconazole has the least effect on hepatic microsomal enzymes
•Thus, has a wide therapeutic window.
•Fluconazole is the azole of choice in the treatment and secondary
prophylaxis of cryptococcal meningitis.
•It is also effective for mucocutaneous candidiasis

Echinocandins
•Inhibit the formation of 1,3-β-D-glucans in the fungal cell wall by
inhibiting the activity of the glucan synthase complex
•The inhibition of glucan synthesis reduces structural integrity of
the fungal cell wall, resulting in osmotic instability and cell death.

Echinocandins …
•Three echinocandins are approved for clinical use: caspofungin,
anidulafungin, and micafungin.
•differ somewhat pharmacokinetically but all share
lack of oral bioavailability
extensive protein binding (>97%)
 inability to penetrate into CSF
lack of renal clearance, and
only a slight to modest effect of hepatic insufficiency on plasma
drug concentration
•All three agents are
pregnancy Category C.

Other topical antifungals
•White field ointment
–Benzoic acid + salicylic acid
•Salts of long chain fatty acids
–Zinc undecylinic acid

Antineoplastic agents

Cancer
•Cancers account for 20-25% of deaths in clinical practices.
•Cancer is a disease characterized by a loss in the normal control
mechanisms that govern cell survival, proliferation, and
differentiation.
•Cancer cells are also referred to as tumors or neoplasms
•Tumors result from a single abnormal cell, which continues to
divide indefinitely
•Cancer is characterized by
uncontrolled growth, ability to
invade local tissues, and ability to spread or metastasize

Cancer..
The mechanism of carcinogenesis is multistage and multi factorial
process that involves both genetic and environmental factors
Initiation: The first step involves the exposure of normal cells to a
carcinogen producing genetic damage to a cell
Promotion: The environment becomes altered to allow preferential
growth of mutated cells over normal cells.
The mutated cells becomes cancerous
Progression: Increased proliferation of cancer cells allows for invasion
into local tissue and metastasis
“Genetics loads the gun; the environment pulls the
trigger”

Types of cancer
•Depending on the location cancer can be classified into two
(a). Solid tumors
•Carcinomas are tumors of epithelial cells e.g lung, colon, breast
•Sarcomas include tumors of connective tissue such as bone
(osteosarcoma) or muscle (liomyosarcoma)
(b).
Hematological malignancies
•Lymphomas are tumors of the lymphatic system and include
Hodgkin and non-Hodgkin lymphomas
•Leukemias are tumors of blood-forming elements and are
classified into acute or chronic

Causes of cancer
Viruses: Epstein-Barr virus, HBV and human papilloma virus
Environmental and occupational exposures such as ionizing
and UV radiation and exposure to chemicals including vinyl chloride,
benzene, and asbestos
Lifestyle factors such as high fat, low fiber diets, tobacco and
ethanol use
Medications including alkylating agents and immuno-suppressants
Genetic factors including inherited mutations, cancer causing
genes (oncogenes), and defective suppressor genes

Molecular mechanisms of cancer
All the causes of cancer finally leads to abnormality in the expression
of proto-oncogenes
Proto-oncogenes are normal genes that can become oncogene due
to mutations or increased expression
Proto-oncogenes code for proteins that help to regulate cell growth
and differentiation
The mutation of these genes to oncogenes in a sequential, multistep
process leads to cancer

Cell cycle
•Tumor cells can be classified as proliferating cells and non-
proliferating cells.
•The ratio of proliferating cells in the whole tumor tissue is
called growth fraction (GF).
•The faster the tumor cells proliferate, the bigger the GF
is and the higher the sensitivity of tumor to a drug.
•Generally, in the early stage, the GF of a tumor is bigger and
the effect of a drug on the tumor is better.

Proliferating cells
cycle of tumor cells can be divided into 4 phases
•Pre-synthetic phase (Gap 1 phase or G1 phase)
–RNA and proteins required for the specialized function of the
cell are synthesized
•Synthetic phase (S phase): cells are synthesizing their DNA.
•Post-synthetic phase (Gap 2 phase or G2 phase).
–DNA duplication has been finished and they are equally divided
to the two of future sub-cells.
–RNA, critical proteins, and the mitotic spindle apparatus are
produced

Cell cycle …
•Mitosis phase (M Phase).
–Each cell is divided into two subcells.
–of these new cells enter the new proliferating cycle, the others
become non-proliferating cells.
•Some anticancer drugs are cell cycle phase-specific
Antimetabolite anti-cancer agents damage the cell in the S phase
Mitosis inhibitors have their maximum effect in the M phase
•Other antineoplastic agents such as DNA alkylating agents and most
antineoplastic antibiotics are toxic to cells regardless of the phase of
the cycle

Non-proliferating cells
•include G
0 phase cells (resting-phase cells)
•G
0 phase cells have proliferation ability but do not divide
temporally.
•When proliferating cells are suffered heavy casualties,G
0 phase
cells will get into proliferating cycle and become the reasons of
tumor recurrence.
•G
0 phase cells are usually not sensitive to antineoplastic
drugs, which is the important obstacle to tumor
chemotherapy

Cell cycle ….

Antineoplastic agents
Antineoplastic means against new growth
Generally, all antineoplastic agent act by interfering with
cellular synthesis or the function of RNA, DNA, and the
proteins that sustain life
All antineoplastic agents are designed to kill cells, therefore
not specific to cancer cells
An ideal therapeutic agent would only destroy cancer cells
only

Antineoplastic agents …
Antineoplastic agents nonspecifically destroy the rapidly
dividing cells of:
GIT leading to severe nausea and vomiting
hair follicles resulting in alopecia
bone marrow leading to fatigue

Treatment of Cancer
The specific approach used to treat cancer depends upon the
specific type of cancer, location, and its stage.
However, in most therapeutic approaches there will be a
contribution of a chemical anticancer compound.
1)Surgery: be applied
when cancer is still in the primary stages and
when be sure that the entire tumor can be excised without
causing significant damage of the vital organs.
Surgery can also be used for diagnostic purposes.

Treatment of Cancer ….
2) Radiation therapy
•may be superior to surgeries in case of cancer of larynx. It can
destroy microscopic cancer cells after surgery.
•Before surgery it reduces tumor and decreases metastasis.
•Because ionizing radiation is carcinogenic, radiation therapy is
subjected to limitations.
•Radiation sensitizers are of help to increase damaging effect of
radiation without increase in radiation dose. e.g. 5-fluorouracil,
dactinomycin, misonidazole and razoxane

Treatment of Cancer ….
3) Immunotherapy
Stimulate the body’s own defenses to destroy the last few
cancer cells remaining after surgery, radiotherapy or
chemotherapy.
attempts to boost the levels of lymphocytes, specifically T-cells
and B-cells lymphocytes.
T- cells destroy foreign cells, including malignant and
premalignant cells.
B-cells make antibodies in response to a foreign protein which
may be expressed by cancer cells.
Therapy of this type consists of the
administration of IFs.

Treatment of Cancer ….
4) Chemotherapy
The intent of administering these agents may to
cure a specific cancer
reduce the size of a tumor prior to surgery
sensitize tumors to radiation therapy or
to destroy microscopic metastases after tumors are surgically
removed.
Chemotherapeutic agents are complementary to either surgery or
radiation therapy.
Their usefulness in treatment of cancer relies on the assumption
that malignant cells, which are rapidly proliferating cells, take-up
extra cellular materials at a great rate than the normal cells.

Treatment of Cancer ….
•However there are few normal cell types that are rapidly
proliferating including hair cells, bone marrow cells and cells
lining the gastrointestinal tract.
•Consequently, patients undergoing chemotherapy, suffer hair loss,
depression of their immune system, nausea or diarrhea.
However, chemotherapeutic agents have some drawbacks:
They are less useful for large tumors since such tumors are not
well perfused with blood.
They are basically cytotoxic and can kill normal cells too.

Treatment of Cancer ….
5) Gene Therapy
•is the treatment of any condition through the transfer of
genetic material.
•Gene delivery systems are based on viral and non viral
approaches.
•Non viral approaches involve small liposomes, which can
bypass the reticular endothelial system in the liver and
therefore remain in the circulation for a long period of time.
•They can enter tumor tissue due to the increased
permeability of tumor vessel walls and may be used as
tumor target transport vehicles for DNA or drugs.

Treatment of Cancer ….
The gene therapy can be divided into three groups:
a) Introduction of suicide genes: A strategy employs the delivery to
tumor cells of genes encoding product-converting enzymes and then
treatment with systemic administration of the respective nontoxic
prodrug. This approach is termed suicide gene therapy.
b) Replacement of defective tumor suppressor genes:
•This strategy tends to replace either a missing or muted defective gene.
•However, it is less effective if cancer is oligo- or multygenic in origin.
c) Genetic immuno-potentiation:
•Malignant cells show antigenic differences to normal cells. However their
immunogenicity is not recognized by the host’s immune system.

Cancer chemotherapy
•is the use of drugs to inhibit or kill proliferating cancer cells,
while leaving host cells unharmed, or at least recoverable.
Cancer treatment modalities
•Chemotherapy is presently used in three main clinical settings:
a)Primary induction TX:
–For advanced disease or
–For cancers for which there are no other effective TX
approaches

Cancer treatment modalities …
b)Neoadjuvant TX:
–For pts who present with localized disease, for whom local forms of
therapy such as surgery or radiation, or both, are inadequate by
themselves
c)Adjuvant TX:
–An adjuvant to local methods of TX, including surgery, radiation
therapy, or both
–Chemotherapy kills the microscopic rests of cells adjacent to
primary tumor outside the surgical margin and the distant metastasis.
–Both of these cells are in infancy stage and are highly susceptible to
drugs

Classification of Antineoplastic Drugs
•On the basis of anti-neoplastic action on the phase of
proliferation cycle, drugs are classified as
•cell cycle non-specific agents (phase nonspecific agents,
CCNSA)
–e.g. alkylating agents
–Act in all proliferating phases, even the G
0
–effects are stronger.
•Cell Cycle specific agents (phase specific agents,CCSA).
–e.g. Antimetabolites, vinca alkaloids
–just act on specific phases of the cell cycle
–effects are comparatively weaker.

Classification ….
•On the basis of source and action mechanisms, the
drugs are also classified as:
alkylating agents
antimetabolites
natural products
hormones and antagonists
miscellaneous agents

1. ALKYLATING AGENTS
•Are electrophiles that can replace a hydrogen atom by an alkyl group under
physiological conditions
•but the term is usually more broadly interpreted to include any compound
that can replace hydrogen under these conditions, including metal complexes
forming coordinate bonds
•contain chemical groups which have the ability of forming covalent bonds with
nucleophilic substances in the cell (DNA, RNA and certain enzymes).
•Most of the anticancer alkylating agents are bifunctional; possessing two
alkylating groups.
•They are thus able to react with two groups and can cause intra- or inter-chain
cross-linking, that can interfere with transcription and replication of DNA.

ALKYLATING AGENTS: mechanism of action
•transfer of alkyl groups to various cellular constituents - cytotoxic.
•Alkylations of DNA with in the nucleus-major interactions -cell death.
•However, these drugs react chemically with sulfhydryl, amino,
hydroxyl, carboxyl, and phosphate groups of other cellular
nucleophiles as well.
•A secondary mechanism that occurs with nitrosoureas involves
carbamoylation of lysine residues of proteins through formation of
isocyanates.

Mechanism of action …
•The major site of alkylation within DNA is the N7 of guanine
•Other bases are also alkylated to lesser degrees, including N1 and
N3 of adenine, N3 of cytosine, and O6 of guanine, phosphate atoms
and proteins associated with DNA.
•These interactions can occur on a single strand or on both strands
of DNA through cross-linking, as most major alkylating agents are
bifunctional, with two reactive groups
•Alkylation of guanine can result in miscoding through
abnormal base
pairing with thymine or in depurination by excision of guanine
residues.

Mechanism of action …
•The latter effect leads to DNA strand breakage through
scission of the sugar-phosphate backbone of DNA.
•Cross-linking of DNA appears to be of major importance to the
cytotoxic action of alkylating agents, and replicating cells are most
susceptible to these drugs.
•Thus, although alkylating agents are not cell cycle specific, cells are
most susceptible to alkylation in late G1and S phases of the cell
cycle.

Mechanism of action …

Alkylating Agents: Resistance
•Increased capability to repair DNA lesions
•Decreased transport of the alkylating drug into the cell
•Increased expression or activity of glutathione and
glutathione-associated proteins, which are needed to
conjugate the alkylating agent, or
•Increased glutathione S-transferase activity, which catalyzes
the conjugation.

Alkylating Agents: Adverse Effects
•are generally dose-related
•occur primarily in rapidly growing tissues such as bone
marrow, gastrointestinal tract, and reproductive
system.
•Nausea and vomiting can be a serious issue
•they are potent vesicants and can damage tissues at the
site of administration as well as produce systemic toxicity.
•are carcinogenic in nature, and there is an increased risk of
secondary malignancies, especially acute myelogenous
leukemia

Classification of alkylating agents
A. Nitrogen mustards
B. Nitrosoureas
C. Aziridines
D. Sulfonic acid esters
E. Triazines
F. Platinum complexes

alkylating agents ….
A. Nitrogen Mustards
•Their original use stems from the observation during world
war I, that individuals heavily exposed to mustard gas suffered
damage to bone marrow and lymphoid tissues.
•Mustard gas: highly toxic, insoluble in water.
•Nitrogen mustard derivatives: less toxic, salts are solids
and water soluble.

Cl
N
Cl
R

Nitrogen Mustards …
Chlorambucil
•is an alkylating agent used for its antineoplastic properties in the
treatment of leukemias, lymphomas and various other malignant
neoplasms.
•is the slowest acting and least toxic nitrogen mustard.
•Adverse effects include: bone-marrow depression, GIT
disturbances, neurotoxicity, lung disorders and sterility.
- It is administered orally.

Nitrogen Mustards …
Cyclophosphamide
• is an alkylating antineoplastic agent, which can be given by mouth
or by intravenous injection:
•Although it is chemically related to the nitrogen mustards, the
nucleophilicity of the mustard nitrogen is less likely to form an
aziridinium ion than are the alkyl-substituted nitrogen mustards.
•It requires activation in the body to take effect.
P
N
O
O
N
Cl
Cl

Bio-activation of Cyclophosphamide
•It is inactive in its parent form, and must be activated to cytotoxic
forms by liver microsomal enzymes
•It must be enzymatically oxidized to give an active metabolite, which
is converted to 4-hydroxycyclophosphamide and
aldophosphamide.
•aldophosphamide is chemically unstable, undergoing conversion to
acrolein and phosphamide mustard.
•Acrolein causes urotoxicity, therefore Mesna which is acrolein
antidote should be given
•Mesna is water soluble and forms a non-toxic product with
acrolein.

Cyclophosphamide metabolism

Cyclophosphamide:
Clinical use
•It is administered as tablets.
•is used in the treatment of various malignant diseases including
lymphoma, myeloma and a variety of solid tumors.
Adverse effects
•include myelosuppresion and hemorrhagic cystitis (which may be
prevented with mesna) as well as GIT, pulmonary, and cardiac
toxicity, alopecia and sterility.

alkylating agents ….
B. Nitrosoureas
Carmustine (BCNU)
•is a neutral molecule that is highly lipophilic and poorly soluble in water.
•These properties allow for efficient crossing of blood-brain barrier.
•Although carmustine administration is thought to alkylate DNA and
RNA as a mechanism of action, it is not cross resistant with nitrogen
mustards and alternate mechanisms of action involving enzyme
inhibition by carbamoylation of proteins have been suggested

Carmustine …
•It is rapidly metabolized after intravenous administration to
form metabolites that have antineoplastic activity.
•These are vinyl cation, the ultimate alkylating agent and 2-
chloroethylisocyanate which gives 2-chloroethylamine, an
additional alkylating agent

C. Aziridines (Ethyleneimines)
•Aziridine is a 3 membered nitrogen heterocycle that reacts with
nucleophiles in order to relief ring strain.
•At acidic pH, the aziridine group is protonated to provide a
reactive aziridinium ion that is known to alkylate DNA.
N
N
N
N
N
N
Triethylenemelamine (TEM, Tetramine)
2,4,6-Tris(1-aziridinyl)-s-triazine
N
NNP
S
Thiotepa
Tris(1-aziridinyl )phosphine sulfide
N
NNP
O
Toxic metabolite

Aziridines ….
•used in carcinoma of breast, bladder, Hodgkin’s and non-
Hodgkin’s lymphoma.
•Metabolic desulfuration leads to a toxic metabolite

D. Sulphonic Acid Esters
Busulphan (Myleran) (1,4-Butanediol dimethylsulfonate)
•is an alkylating agent with a methanesulfonic acid acting as a leaving
group.
•is used to treat chronic
myelocytic leukemia.
•is formulated as tablets.
•Adverse effects include prolonged and sometimes irreversible
bone-marrow depression, and pulmonary fibrosis.
S
O
O
S
CH 3
H
3C
O
O
O
O

E. Platinum compounds
i. Cisplatin (Platinol) ii. Carboplatin
(Paraplatin)

O
P t
O
O
O
Cis-Dichlorodiaminoplatinum (II)
It is less toxic than cisplatin
and used in ovarian cancer.

Platinum compounds …..
Chemical structures of cisplatin,
carboplatin, oxaliplatin, satraplatin, and
picoplatin
Schematic image illustrating the G-GDNA intrastrand cross-links
produced by cisplatin or carboplatin,
oxaliplatin, satraplatin, and picoplatin

Cisplatin
•It is a platin complex containing two ammonia molecules and two
chlorine atoms in a cis configuration.
•It reacts with nitrogen atoms of DNA preferentially with N7 of
deoxyguanylic acid forming intrastrand and interstrand cross-links.
•It is active against
testicular cancer, lymphoma, carcinoma of the
head and neck, ovarian cancer and bladder cancer, However it
induces renal and neurotoxicities.
•It is administered intravenously.
•Transplatin is inactive as it lacks the stereochemistry
required for cross linking.

Cisplatin: Mechanism of Action
Pt
H
3N
Cl
Cl
H
3N
H
2O
Pt
H
3N
Cl
H
3N N
N
N
N
NH
2
O
H
Sugar
7
N
N
N
N
NH
2
O
Pt
H
3N
Cl
NH
3
Sugar
Sugar
N
N
N
N
NH
2
O
Pt
H
3
N
NH
3
H
2
O
H
2O
N
N
N
N
O
H
2N
Sugar
7
OH
2
7
+
+
7 7
Sugar
N
N
N
N
O
H
2N
N
N
N
N
NH
2
O
Pt
H
3
N
NH
3
Sugar
DNA adduct
Cross link

2. ANTIMETABOLITES
•Antimetabolites are compounds that prevent the
biosynthesis or utilization of normal cellular
metabolites.
•They are closely related in structure to the metabolite being
antagonized.
•Many antimetabolites are enzyme inhibitors.
•They may combine with the active site as if they are the
substrate or cofactor.

ANTIMETABOLITES ….
A. Folic acid Antagonists (antifolates)
•Folic acid is essential for the synthesis of nucleic acids.
•It is reduced to dihydrofolic acid (DHFA) then to tetrahydrofolic
acid (THFA) by folate reductase.
•Tetrahydrofolic acid picks up a methyl group from serine or
methionine and is converted into N5,N10-methylene
tetrahydrofolic acid.

Antifolates …..
Methotrexate (MTX)
• is a folic acid analog that binds with high affinity to the active
catalytic site of dihydrofolate reductase (DHFR).
•This results in inhibition of the synthesis of tetrahydrofolate (THF),
the key one-carbon carrier for enzymatic processes involved in de
novo synthesis of thymidylate, purine nucleotides, and the
amino acids serine and methionine.
•Inhibition of these various metabolic processes thereby interferes
with the formation of DNA, RNA, and key cellular proteins

Methotrexate (MTX) …
•Intracellular formation of polyglutamate metabolites, with the
addition of up to 5–7 glutamate residues, is critically important for
the therapeutic action of MTX, and
•this process is catalyzed by the enzyme folylpolyglutamate synthase
(FPGS).
•MTX polyglutamates are selectively retained within cancer cells,
and they display increased inhibitory effects on enzymes involved in
de novo purine nucleotide and thymidylate biosynthesis, making
them important determinants of MTX’s cytotoxic action.

Methotrexate (MTX): resistance
•decreased drug transport via the reduced folate carrier or folate
receptor protein
•decreased formation of cytotoxic MTX polyglutamates
•increased levels of the target enzyme DHFR through gene
amplification and other genetic mechanisms
•altered DHFR protein with reduced affinity for MTX.
•decreased accumulation of drug through activation of the
multidrug resistance transporter P170 glycoprotein may also
result in drug resistance.

Antifolates …..
B. Purine Antagonists
•Include: 6-Mercaptopurine (6MP) and 6-thioguanine (6TG)
•Both are not active until they are converted to their respective
nucleotides by a pyrophosphorylase enzyme in the cell.
•Since this is an intrinsically destructive process to the cell, it is
referred to as a lethal synthesis.
•Absence of this enzyme function is not lethal to the cell since the
synthesis of purines in the cell occurs by different pathways.
•They interfere with the de novo synthesis of purines.

Co-Administration of Allopurinol with 6-Mercapotopurine
•6MP is metabolized by xanthine oxidase (XO) to 6-thioxanthine
then to 6-thiouric acid, while 6TG is not affected by this enzyme.
•On the other hand, XO is responsible for the oxidation of
hypoxanthine to uric acid which deposits in joints leading to gout.
•Allopurinol is a structural isomer to hypoxanthine and is a
xanthine oxidase inhibitor but is not uricosuric acid. •When allopurinol is given with 6MP, it will prevent the metabolic
effect of the enzyme on 6MP, consequently the normal dose of
6MP will be toxic.

C. Pyrimidine Antagonists
5-Fluorouracil (5FU)
•is inactive in its parent form and requires activation via a complex series
of enzymatic reactions to ribosyl and deoxyribosyl nucleotide
metabolites.
•5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), forms a
covalently bound ternary complex with the enzyme thymidylate synthase
and the reduced folate 5,10-methylenetetrahydrofolate
•This results in inhibition of DNA synthesis through “thymineless death.”
•5-fluorouridine-5′-triphosphate (FUTP), incorporated into RNA,
where it interferes with RNA processing and mRNA translation.

3. HORMONES and ANTIHORMONES
•Tumors derived from hormone-sensitive tissues may be hormone
dependent.
•Their growth can be inhibited by hormones of opposing actions, by
hormone antagonists or by agents that inhibit the synthesis of the
relevant hormone.
•Hormones essential for reproduction are also responsible for
development and growth of breast, prostate and uterine cancer.

A. Hormone-Dependent Breast Cancer
•Estrogens bind to an estrogen receptor in estrogen target site
(uterus, vagina, pituitary gland) to give E-R complex with
subsequent response.
•The more is the cells in the tumor that contain estrogen; the
higher is the estrogen receptor content.
•The tumor is said to be estrogen receptor rich (estrogen receptor
positive).
•This tumor type responds well to endocrine therapy
(antiestrogen).

Breast Cancer ….
•On the other hand, tumor with low estrogen receptors is said to
be estrogen poor (estrogen receptor negative) responds poorly to
endocrine treatment.
•Ethinylestradiol is given orally in the treatment of breast cancer in
post menopausal women.
•Androgens are active against metastatic breast cancer about 20%
of postmenopausal women
•Progesterone and its analogs are active against certain neoplasms
that are stimulated by estrogens. High doses of progestines or
androgens antagonize the proliferative action of estrogen.
-

Tamoxifen
•It is selective estrogen receptor modulator used in the treatment
of the advanced breast cancer.
•In breast tissues, tamoxifen competes with endogenous estrogen
for the estrogen receptor and inhibits the transcription of
estrogen-responsive genes.
•It is bioactivated first to produce the active hydroxylated
derivative.

B. Hormone-Dependent Prostatic Cancer
•Most of prostatic tumors are androgen-dependent.
•The action of androgens in prostate involves metabolic activation
of circulatory androgens to a derivative with high binding affinity
for androgen receptors.

•Flutamide has antiandrogenic activity and used to treat
prostate cancer

4. ANTIBIOTICS
•Several compounds that were originally evaluated for their antibiotic
activity have been clinically useful anticancer agents.
•However, they were rejected as antibiotics because of their toxicity.
•This property was subsequently turned into asset with their
application as anticancer agents.
•The source of most antitumor antibiotics is from microbial
fermentation.

ANTIBIOTICS …
Anthracyclines
•These antibiotics represent a major class of antineoplastic agents.
•It is characterized by having a tetracyclic quinone containing ring
nucleus to which is attached a unique daunosamine sugar.
•It was isolated from the fermentation broths of Streptomyces
peucetius.
•Several semisynthetic derivatives have been prepared in an attempt
to reduce the cardiotoxicity common to this class of compounds.
•These include daunorubicin, doxorubicin, idaurubicin and
epirubicin.

Anthracyclines ….
Mechanism of action
•The flat structure of anthraquinone nucleus results in the ability of
anthracyclines to interact with DNA perpendicularly to its long
axis.
•The amino sugar confers added stability to this binding through its
interaction with the sugar phosphate backbone of DNA.
•The results of interaction can lead to single- and double-
stranded DNA breaks.

Anthracyclines ….
•Because of the anthraquinone ring system, the anthracyclines are
capable of generating reactive oxygen species such as .OH radical
and super oxide radical anions( .O-O- ).
•These free radicals produce destructive effects upon the cell.
•The generation of free radicals may also account for the
cardiotoxicity of the anthracyclines.
• Due to lack of oral activity, they are administered intravenously.

Antibiotics ….
ii. Bleomycins
•are a group of metal-chelating glycopeptide antibiotics that degrade
DNA; its molecule features two pivotal domains.
1. One is the DNA domain, w/c allows interaction with DNA and
RNA.
2. The second binding site is a metal binding domain which is involved
in chelation of ferrous iron and interaction with the oxygen, resulting
in the oxidation of the iron and generation of superoxide.
•It is used for the treatment of
squamous cell carcinomas of the
head and neck.

Antibiotics ….
iii. Dactinomycin (Actinomycin D)
•It consists of tricyclic phenoxazone ring and two identical
pentapeptide lactones.
•The pentapeptides are made up of L-proline and L-threonine plus
the essential amino acids D-valine, sarcosine and N-methylvaline.
•The ring system is planar and can intercalate or insert into DNA
between base pairs.

•The distortion caused by the presence of the intercalating agent
affects the action of topoisomerase II, which normally regulates
unwinding of coiled double-stranded DNA.
•-This in turn, interferes with DNA replication and transcription.

5. PLANT PRODUCTS (ANTIMITOTIC AGENTS)
•These agents prevent cellular mitosis, and in particular, interfere
with the formation of the mitotic spindle.
•During mitosis; the protein tubulin undergoes polymerization to
form mitotic spindle.
•Antimitotic agents interfere with this either by
depolymerization of the microtubules or by causing structures
other than the normal mitotic spindle to be formed.
•In the absence of a properly formed mitotic spindle, the
chromosomes cannot correctly segregate and this ultimately leads
to cellular death.

PLANT PRODUCTS : ANTIMITOTIC AGENTS …….
i. Vinca Alkaloids: Vincristine, Vinblastin and Vinorelbine
•These alkaloids are composed of two multi ringed units.
•The vinca alkaloids contain tertiary amino groups that form salts
which are freely soluble in water.

Vinca Alkaloids: Mechanism of action
•involves inhibition of tubulin polymerization, which disrupts
assembly of microtubules, an important part of the cytoskeleton
and the mitotic spindle.
•This inhibitory effect results in mitotic arrest in metaphase,
bringing cell division to a halt, which then leads to cell death.

PLANT PRODUCTS : ANTIMITOTIC AGENTS …….
ii. Taxans
•Paclitaxel and docetaxel are taxan derivatives of yew tree black.
•Docetaxel is active in patients with breast cancer resistant to
anthracyclines.
•Both derivatives are excellent choices for the first and second line
treatment of patients with metastatic breast cancer.
•Paclitaxel is administered intravenously in non aqueous solution.
•The injectable solution must be diluted prior to use.

6. MISCELLANEOUS ANTICANCER AGENTS
Podophyllotoxins
They are obtained as extracts of the May apple plant, used to treat
small cell carcinomas of the lung and Hodgkin’s diseases.
They cause DNA linkages or DNA strand breaks by inhibiting
topoisomerase II.
It may be applied topically as paint.

Endocrine Pharmacology

1

Introduction
The endocrine system
Controls the flow of information b/n d/t cells & tissues
Denotes internal secretion of biologically active substances
Subject to complex regulatory mechanisms that govern
hormone synthesis, release, transport, metabolism & delivery
2

The Endocrine System
3

4

Types of glands
Autocrine glands: local to same cells that released the
hormone
Paracrine glands: local to adjacent cells
Endocrine glands: release into interstitial space, lymphatics
and blood
Pheromone glands: secrete into the air
5

What is an endocrine hormone?
A specific chemical compound
Produced by a specific tissue of the body
Where it is released into the body fluids
And carried to a distant target tissue
Where it affects a pre-existing mechanism
And is effective in small amounts
6

7

Thyroid Hormones & Antithyroids
8

The thyroid gland
•Member of the Endocrine System
–Secretes three main hormones
•Tri-iodo thyronine (T
3)
•Thyroxine (T
4) regulate metabolism and growth
•Calcitonin regulate plasma Ca
+2
–Located in the neck adjacent to the 5
th
cervical vertebra (C5)
–Composed of
thyroid follicular cells w/c specialize in the
absorption of iodine and secretion of thyroid hormones

9

Major steps in the biosynthesis are: regulated by TSH
Uptake of iodide (I
-
) by the gland; regulated by TSH, by increasing
expression of NIS
Oxidation of iodide & iodination of tyrosyl groups Tg;
Coupling of iodotyrosine residues by ether linkage to generate the
iodothyronines;
Resorption of the Tg colloid from the lumen into the cell
Proteolysis of Tg & release of T4 & T3 into blood
Recycling of the iodine within the thyroid cell via de-iodination of
mono- & di-iodotyrosines & reuse of the I
-
&
Conversion of T
4 to T
3 in peripheral tissues & thyroid
10

11

Regulation of thyroid hormone
•The secretion of thyroid hormone is regulated by
TRH from hypothalamus releases TSH from the anterior
pituitary.

Negative feedback effect of T
3 & T
4

Plasma iodide concentration
12

13

Treatment of Hypothyroidism
The only effective treatment of hypothyroidism, unless it is due
to iodine deficiency (treated with iodide) is to administer the
thyroid hormones themselves
–Thyroxin (levothyroxine, T
4) is the standard replacement
therapy
–Triiodothyronine (liothyronine, T
3) being reserved for the
rare condition of myxedema coma when its more rapid
action is required for emergency treatment

14

Levothyroxine Sodium
Sodium salt of the naturally occurring levorotatory isomer of
T4
Preparation of choice for maintenance of plasma T4 and T3
concentrations
It is absorbed intact from the GIT, and its long half-life allows
for convenient once daily administration
The aim is to establish euthyroidism with measured serum
concentrations of T4, T3, and TSH within the normal range

15

Liothyronine Sodium
Liothyronine is generally not used for maintenance thyroid
hormone replacement therapy
 its short plasma half-life and duration of action
The use of T
3 alone is recommended only in special situations,
such as in
the initial therapy of myxedema
short-term suppression of TSH in patients undergoing
surgery for thyroid cancer
Useful in 5-deiodinase deficiency
16

Hypothyroidism treatment cont…
Liotrix
–is a 4:1 mixture of levothyroxine sodium and liothyronine
sodium
–used for thyroid hormone replacement therapy in hypothyroid
patients
–does not appear that liotrix offers any therapeutic advantage
over levothyroxine alone
17

Adverse effects of treatment with thyroid hormone
The most common adverse effects are the result of drug
overdose; they include:
–Cardiac palpitation and arrhythmias, tachycardia,
–Weight loss, tremor, headache, insomnia, and heat
intolerance
 Symptoms subside if medication is withheld for several days
18

Thyrotoxicosis (Hyperthyroidism)
Thyrotoxicosis results when tissues are exposed to excessive
levels of T4, T3, or both
TSH-secreting pituitary tumors release biologically active
hormone that is unresponsive to normal feedback control
The tumors may co-secrete prolactin or growth hormone;
therefore, patients may present with amenorrhea, galactorrhea,
or signs of acromegaly
19

Hyperthyroidism…
Treatment options
–Surgical removal of the gland
–Radiation therapy I
131
(radioisotope of I)
–Antithyroids
20

Radiation therapy
Radioiodine (I
131
): works by destruction of the gland by beta
particles emitted
First line treatment
Half-life of eight days
Used in one single dose
Hypothyroidism will eventually develop, but is easily managed by
replacement therapy with thyroxin
Should be avoided in
children and also in pregnant patients
because of potential damage to the fetus
21

Antithyroids
Thioureas/Thioamides/: carbimazole, methimazole, PTU
MOA: in the thyroid gland, they inhibit the activity of the enzyme
TPO, w/c is required for;
The intra-thyroidal oxidation of I
The incorporation of I into Tg, and
The coupling of iodotyrosyl residues to form thyroid hormones
Also inhibit peripheral conversion of T4 to T3
22

Pharmacokinetics
They are well absorbed from the gastrointestinal tract
Have short plasma t1/2 (PTU=2hrs; methimazole=8-12 hrs)
Single daily dose may exert effects for greater than 24hrs
Undergo hepatic conjugation & excreted in the bile & urine
Few enterohepatic circulation
23

Clinical Use
Hyperthyroidism
Thyrotoxic crisis and
For preparation of patients to surgical thyroidectomy
Require 3-4 wks to take effect (until store is depleted)
Although thioamides (PTU) may be used during pregnancy, they
should be given in minimally effective doses to avoid
Inducing infantile hypothyroidism and
Thyroid enlargement in the developing fetus
24

Adverse effects
Hypothyroidism and enlargement of the thyroid gland
Granulocytopenia and agranulocytosis
Rash, arthralgia, myalgia, cholestatic jaundice,
Lymphadenopathy (abnormal enlargement of lymph nodes)
Drug fever, psychosis, and a lupus like syndrome (ulcerative
skin disease)
25

Iodine
It is converted in-vivo to iodide which temporarily inhibits the
release of thyroid hormones
When high doses of iodine are given to thyrotoxic patients, the
symptom subsides within 1-2 days
There is inhibition of secretion of thyroid hormones and over
a period of 10-14 days, a marked reduction in vascularity of the
gland, which becomes smaller and firmer
Iodine solution in KI (Lugol’s iodine) is given orally
26

MOA:
High concentration limits its own transport & it prevents
iodination process
It inhibits release of the thyroid hormone
Iodide alone is not used for the mgt of hyperthyroidism
Rebound thyroid hormone secretion & thyrotoxicosis may
return at previous or more severe intensity
KI + PTU: management of thyrotoxic crisis
Iodide + thioamide: for surgical thyroidectomy
27

ADRs to iodine can be divided into;
Intra-thyroidal reactions
–Iodine-induced thyrotoxicosis
–Hypothyroidism
Extra-thyroidal reactions
–Rash, drug fever; inflammation of the salivary gland
–Conjunctivitis and rhinitis
–Vasculitis
28

29

Potassium Perchlorate
The perchlorate ion of potassium perchlorate, KClO4, is a
competitive inhibitor of thyroidal I transport via the Sodium
Iodide Symporter (NIS)
This drug can cause fatal aplastic anemia and gastric ulcers
and is now rarely used
effective in treating iodine-induced hyperthyroidism
30

Others
Include
–Beta adrenoceptor antagonists
e.g. propranolol
•For blunting the widespread sympathetic stimulation.
–Guanethidine: a noradrenergic blocking agent
•To ameliorate the exophthalmia, eye drops, act by relaxing the
sympathetically innervated smooth muscle that causes eyelid
retraction.
–Glucocorticoids
e.g. predinsolone for the exophthalmia of Graves disease
31

Corticosteroids
32

Introduction
Adrenal gland: medulla and cortex
Medulla: secretes catecholamines
Cortex: secretes two types of corticosteroids
(glucocorticoids and mineralocorticoids) and the adrenal
androgens.
•Mineralocorticoids (aldosterone): regulate salt and
water metabolism
•Glucocorticoids (for example, cortisol): that are
involved with metabolism and response to stress
33

Glucocorticoids
get their name from their effect of raising the level of blood
sugar (glucose).
•by stimulating gluconeogenesis in the liver.
The principal human glucocorticoid is cortisol (also called
hydrocortisone).
•Normally, its production is diurnal, with a peak early in the
morning followed by a decline and then a secondary, smaller
peak in the late afternoon.
•Factors such as stress and levels of the circulating steroid
influence secretion
34

Cortisol (Hydrocortisone)
Naturally occurring glucocorticosteroid
Pharmacokinetics
•Daily secretion, in the absence of stress,10-20 mg of cortisol.
•Cortisol bound to circulating proteins like Corticosteroid-binding
globulin (CBG)
•Synthetic corticosteroids such as dexamethasone bound to
albumin rather than CBG.

35

Synthetic corticosteroids
They are administered parenterally, orally, topically or inhalation.
Obviously the oral route is preferred for prolonged therapy
However, parenteral administration is required in certain
circumstances.
•IM and IV injections are useful in emergencies.
•Some injections as suspensions are slowly absorbed, which
prolongs effectiveness to
~8 h.
Cortisol, Cortisone, Prednisone, Prednisolone, Fludrocortisone,
Betamethasone and Dexamethasone…..
36

Synthetic corticosteroids
•Prednisone is preferred in pregnancy because it minimizes
steroid effects on the fetus.
•It is a prodrug that is not converted to the active compound,
prednisolone, in the fetal liver.
•Any prednisolone formed in the mother is biotransformed to
prednisone by placental enzymes.
37

Glucocorticosteroids
38
Agent Forms Available
Relative Anti-
Inflammatory
Activity
Relative Salt-
Retaining
Activity
Cortisol (hydro-
cortisone)
Oral, parenteral,
topical
1 1
Cortisone Oral 0.8 0.8
Prednisone Oral 4 0.3
Triamcinolone
Oral, injectable,
topical, inhaled
5 0
Dexamethasone
Oral, injectable,
topical
30 0
Fludrocortisone
(mineralocorticoid
)
Oral 0 250

Therapeutic Uses
Replacement therapy for
Primary adrenocortical insufficiency (Addison disease): Caused by
adrenal cortex dysfunction
Hydrocortisone is given to correct the deficiency
Administration of fludrocortisone may also be necessary to supplement
mineralocorticoid deficiency
secondary or tertiary adrenocortical insufficiency:
Defect in CRH production by the hypothalamus or in ACTH production by
the pituitary.
Hydrocortisone is used for treatment of these deficiencies.
39

Therapeutic Uses cont’d…
Relief of inflammatory symptoms
•Rheumatoid arthritis and inflammatory skin conditions
•Persistent asthma (inhalational)
•Osteoarthritis (intra-articular corticosteroids)
•Corticosteroids are not curative in these disorders
Treatment of allergies:
•Rx of allergic rhinitis, as well as drug, serum, and transfusion
allergic reactions.
40

Therapeutic Uses cont’d…
Acceleration of lung maturation:
•Respiratory distress syndrome is a problem in premature infants.
oFetal cortisol is a regulator of lung maturation
•Consequently, a regimen of betamethasone or
dexamethasone administered intramuscularly to the mother
within the 48 hours proceeding premature delivery can accelerate
lung maturation in the fetus.
41

Therapeutic Uses cont’d…
Other Uses…
Glucocorticoids frequently are used to suppress inflammation in the
eye and can preserve sight when used properly.
Glucocorticoids are valuable in the prevention and treatment of
organ transplant rejection
Glucocorticoids also exert a facilitatory action on neuromuscular
transmission that may contribute to their efficacy in certain
neuromuscular disorders (myasthenia gravis).
42

Adverse effects
Adverse effects are often dose related.
Osteoporosis (↓ed intestinal Ca
2+
absorption, reduced bone formation, and ↓ed
sex hormone synthesis).
Patients are advised to take calcium and vitamin D supplements;
Bisphosphonates may also be useful in the treatment of glucocorticoid-
induced osteoporosis.
Redistribution of body fat, puffy face, hirsutism, and increased appetite
Cataracts may also occur with long-term corticosteroid therapy
Hyperglycemia may develop and lead to diabetes mellitus.
Topical therapy can also cause skin atrophy, ecchymosis, and purple striae.
43

Discontinuation of glucocorticoids
Sudden discontinuation of these drugs can be a serious problem if the
patient has suppression of the HPA axis.
In this case, abrupt removal of corticosteroids causes acute adrenal
insufficiency that can be fatal.
This risk, coupled with the possibility that withdrawal might cause
an exacerbation of the disease, means that the dose must be
tapered slowly according to individual tolerance.
44

Drugs used in Diabetes
45

Drugs used in Diabetes
•The pancreas:
–Exocrine: digestive enzymes
–Endocrine: insulin, glucagon, and somatostatin
46

Low blood
glucose
High blood glucose
Normal blood
glucose level
Glucagon released
by alpha cells of
pancreas
Insulin released by
B cells of pancreas
Liver release
glucose to blood
Fat cells take in
glucose from blood
47

A group of metabolic diseases characterized by high levels of blood
glucose (hyperglycemia)
Diabetes…greek..to pass water
Mellitus….latin…….sweet as honey
characterized by abnormalities in
•Carbohydrates, fats & proteins metabolism
Remains to be
•3
rd
leading cause of death from diseases
•2
nd
leading cause of blindness
•2
nd
leading cause of renal failure

48

•The central problem in DM could be
Reduced or no insulin secretion
Peripheral insulin resistance or
both
•Hyperglycemia is the end point of any type of diabetes mellitus

49

Classification of DM
•ADA recognizes four clinical classifications of diabetes:
1) Type 1 diabetes (formerly, insulin-dependent diabetes
mellitus)
2) Type 2 diabetes (formerly, non-insulin-dependent diabetes
mellitus),
3) Gestational diabetes, and
4) Diabetes due to other causes (for example, genetic defects
or medications).

50

Type 1 DM
•Absolute deficiency of insulin caused by massive β-cell
necrosis
•Autoimmune-mediated processes directed against the β cell
•Shows classic symptoms of insulin deficiency (polydipsia,
polyphagia, polyuria, and weight loss)
•Rely on exogenous (injected) insulin to control hyperglycemia
51

Type 2 DM
•Most diabetic patients have type 2 disease
•Type 2 diabetes is influenced by genetic factors, aging, obesity, and
peripheral insulin resistance, rather than by autoimmune processes
or viruses
•Lack of sensitivity of target organs to either endogenous or
exogenous insulin
•Weight reduction, exercise, and dietary modification decrease
insulin resistance
•Oral glucose-lowering agents then, insulin therapy later
52

Comparison of type 1 and type 2
diabetes
Type 1 Type 2
Age of onset Usually during childhood
or puberty
Commonly over age 35
Nutritional
status at time
of onset

Commonly
undernourished
Obesity usually present
Prevalence 5 to 10 percent of
diagnosed DM
90 to 95 percent of
diagnosed DM
Genetic
predisposition
Moderate Very strong
Defect or
deficiency
β-cells are destroyed,
eliminating the
production of insulin
Inability of β cells to
produce appropriate
quantities of insulin;
insulin resistance; other
defects

53

54
Criteria for the
diagnosis of diabetes
Clinical features of
diabetes at diagnosis

•A phenomena w/c is most common in type I DM
•May occur as a result of stress, infection, and insufficient insulin
taking
•Lipolysis ……. Ketogenesis …ketoniamia ……DKA
•Characterized by
–Metabolic acidosis
–Water and electrolyte depletion
–nausea/vomiting
55

Complications of DM
•Microvascular complication
–retinopathy
–neuropathy
–nephropathy

•Macrovascular complication
–Coronary artery disease
–Peripheral arterial disease
–Myocardial infarction
56

57

Insulin
is the main hormone controlling intermediary metabolism, having
action on liver, muscle and fat
Its overall effect is to conserve fuel by facilitating:
uptake, utilization and storage of glucose, amino acids and fats
after meal
It reduces blood sugar

58

Insulin
59
•Granules within the beta cells store the insulin in the form of crystals consisting of
two atoms of zinc and six molecules of insulin.
•Pre pro insulin (108 AAs)-pro insulin (86AAs)-insulin (51AAs)
•C-peptide- indicter of insulin secretion

Insulin secretion
60

Regulation of insulin release
61

62

Insulin preparations
•Human insulin is manufactured by bacterial recombinant
DNA technology.
•Insulin is indicated for individuals with type 1 diabetes as
well as for those with type 2 diabetes whose hyperglycemia
does not respond to diet therapy and other diabetes drugs.
•Human insulin is dispensed as either regular (R) or Neutral
Protamine Hagedorn (NPH) formulations.
63

Short-acting insulin preparations
A.Regular insulin
–Iv regular insulin: particularly useful in the treatment of
diabetic ketoacidosis and during the perioperative
management of insulin-requiring diabetics.
–Before the development of rapid-acting insulins, it was
the primary form of insulin used for controlling
postprandial glucose concentrations, but it requires
administration 1 h or more before a meal.
64

Short-acting insulin
preparations…
B. Rapidly acting insulin analogs
–Three insulin analogs (insulin lispro, insulin aspart, and
insulin glulisine) have rapid onsets and early peaks of
activity that permit control of postprandial glucose
levels.
–The 3 rapid-acting insulins have small alterations in
their primary amino acid sequences that speed their
entry into the circulation without affecting their
interaction with the insulin receptor.
65

Short-acting insulin
preparations…
B. Rapidly acting insulin analogs…
–The rapid-acting insulins are injected immediately
before a meal and are the preferred insulin for
continuous subcutaneous infusion devices.
–They also can be used for emergency treatment of
uncomplicated diabetic ketoacidosis
66

Intermediate acting insulin
Neutral Protamine Hagedorn (NPH), or isophane
–is a combination of regular insulin and protamine that
exhibits a delayed onset and peak of action.
–The mixture has equivalent concentrations of protamine
and insulin, so that neither is in excess (isophane).
–NPH insulin is often combined with regular and rapid-
acting insulins.
67

Long acting insulins
•are modified forms of human insulin that provide a peak less
basal insulin level lasting more than 20 h, which helps control
basal glucose levels without producing hypoglycemia.
•Insulin glargine
–precipitate at the injection site that releases insulin over an
extended period.
–To maintain solubility, the formulation is unusually acidic (pH
4.0), and
insulin glargine should not be mixed with other
insulins.
68

Long acting insulins…
•Insulin detemir
–the terminal threonine is dropped & has a fatty acid side
chain that enhances self aggregation & association to
albumin.
–the affinity of insulin detemir is four- to five fold lower
than that of human soluble insulin unlike insulin glargine
which has similar affinity with native insulin
69

PK of insulin preparations
70

Onset and duration of action of
insulin preparations
71

Mixtures of insulins
•To control adequately both postprandial and basal
hyperglycemia
•Stable premixed insulins (70% NPH and 30% regular)
•Premixed preparations of rapidly acting insulin analogs
(lispro, aspart) and NPH are not stable because of
exchange of the rapidly acting insulin analog for the
human regular insulin in the protamine complex.

73

Insulin delivery systems
•The standard mode of insulin therapy is subcutaneous
injection (IV in cases of emergency for regular insulin)
•More convenient means of administration are also available.
–Portable pen-sized injectors are used to facilitate
subcutaneous injection.
–Continuous Sc insulin infusion devices avoid the need for
multiple daily injections and provide flexibility in the
scheduling of patients’ daily activities.
74

Site of injection
75 Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9

Dosage regimen
•The total daily dose required is usually 0.5–1.0 unit/kg (about
50 units).
•This is usually divided as 2⁄3 during the day and 1⁄3 at night
for minimum frequency regimens and 50/50 for basal-bolus
regimens.

76

Dosage regimen..
77

Dosage regimen…
78

Dosage regimen..
79

Side effects
Hypoglycemia:- could be due to:
–Too much insulin injected, missed meal, physical exercise
•Treatment to take a sweat drink or snack or if the patient is
unconscious IV glucose (40% solution) or IM glucagon
Allergic reactions
lipodystrophy at injection site i.e. fat accumulation
Hypokalemia
–Potassium supplements or orange juice could be of benefit.
Weight gain

80

Oral antidiabetic Agents
•Anti-diabetic medications treat diabetes mellitus by lowering
glucose levels in the blood.
•With the exceptions of insulin, GLP-1 receptor agonists, and
pramlintide, all are administered orally
–thus also called oral antidiabetic agents
•There are different classes and their selection depends on:
–Nature of the diabetes
–Age, situation of the person & other factors

Classification
Insulin
secretagogues
Sulfonylureas
Meglitinide analogue
Insulin sensitizers
Biguanides
Thiazolidinediones
α-glucosidase
inhibitors
New agents
(GLP-1 Receptor
agonists, DPP4
inhibitors & others)

Sulfonylureas

Mechanism of Action
•The primary mechanism of the sulfonylureas is direct
stimulation of insulin release
– In the presence of viable pancreatic B -cells, sulfonylureas
enhance the release of endogenous insulin
•At higher doses, these drugs also decrease hepatic glucose
production

Sulfonylureas…

•the 2
nd
-generation sulfonylureas may have additional
extra pancreatic effects
increase insulin sensitivity
•The sulfonylureas are ineffective for the management of
type I and severe type II DM
the number of viable cells are absent/very small
•Severely obese diabetics often respond poorly
possibly because of the insulin resistance

Mode of action of sulfonylureas
•sulfonylureas modulate the activity of the K
ATP channels
–by the direct binding to a specific subunit of the K
ATP
channel called SUR1
•Sulfonylurea binding to SUR1 directly promotes the closure of
these K
ATP channels
–lowering the threshold for glucose-dependent insulin
release

Mode of action of sulfonylureas
86

Mode of action of sulfonylureas…
2

Sulfonylureas…

1
st
-Generation Sulfonylureas
•relatively low specificity of action, delay in time of onset,
occasional long duration of action, and a variety of side
effects
•They are occasionally used in patients who have achieved
previous adequate control with these agents.
•Include: acetohexamide, chlorpropamide, tolazamide, tolbutamide

Sulfonylureas…
2
nd
-Generation Sulfonylureas
•higher specificity and affinity for the SUR
•more predictable PK in terms of time of onset and duration
of action
• have fewer side effects & exert mild diuretic effects on the
kidney
•are highly protein bound, primarily through nonionic binding
•Include: Glyburide, Glipizide, Glimepiride, Gliclazide

Sulfonylureas…
Kinetics
•Sulfonylureas are readily absorbed from the GIT
•but undergo varying degrees and rates of metabolism in the
liver and/or kidney
•Some metabolites possess intrinsic hypoglycemic activity
•the biological half-lives of the sulfonylureas vary greatly

Sulfonylureas…
Adverse Effects and Drug Interactions
•The most common adverse effect is hypoglycemia
•sulfonylureas also tend to cause weight gain
–Some of this is due to fluid retention and edema
•The sulfonylurea compounds should be avoided in
individuals who are vulnerable to hypoglycemia
•particularly in renal or hepatic disease (C/I)

Sulfonylureas…

•sulfonylureas are highly bound to plasma proteins
•and are highly metabolized by microsomal enzymes
•Co administration of drugs capable of displacing them from
their protein binding sites or inhibiting their metabolism also
may potentiate hypoglycemia
–(e.g., sulfonamide antibacterials, propranolol, salicylates,
phenylbutazone, chloramphenicol, probenecid, and
alcohol)

Meglitinides

•the meglitinide class of hypoglycemic drugs bind to the same
K
ATP channel
•they are incapable of stimulating insulin secretion in
nutrient
starved B–cells
•in the presence of glucose, they demonstrate hypoglycemic
effects
–by augmenting the release of insulin (not cause fasting
hypoglycemia)

Meglitinides…

•have a rapid onset, a short duration of action & less weight
gain than SUs
•They are categorized as postprandial glucose regulators
•Should not be used in combination with sulfonylureas due to
overlapping mechanisms of action
•metabolized by the liver and should not be used in patients
with hepatic insufficiency.
•The major adverse effect of these drugs is hypoglycemia.
•Include: Repaglinide, Nateglinide, Mitiglinide

Biguanides

•are insulin-sensitizing agents
Metformin
•it increases glucose uptake and utilization by target tissues,
thereby decreasing insulin resistance
•requires insulin for its action, but it does not promote insulin
secretion
•hyperinsulinemia is not a problem
•thus, the risk of hypoglycemia is less

Biguanides…
“Euglycemic,” ↓ postprandial glucose levels, but does not
cause hypoglycemia or weight gain
Pharmacokinetics:
–Metformin is well absorbed orally
–is not bound to serum proteins
–It is not metabolized
–Excretion is via the urine as active compound

Biguanides…
Clinical uses
•as first-line therapy for type 2 diabetes.
•Because metformin is an insulin-sparing agent and does not
increase body weight or provoke hypoglycemia
–Preferred in these patients
•decreases the risk of macrovascular as well as microvascular
disease
•reduces the risk of diabetes in high-risk patients.

Biguanides…
Adverse effects:
–These are largely gastrointestinal (NVD)
–Long-term use may interfere with vitamin B
12 absorption
–Lactic acidosis can sometimes occur with metformin
therapy.
•C/I: GFR < 50 mL/min, CHF, radiographic contrast studies,
seriously ill patients, acidosis
•What is the advantage of metformin over sulphonylureas?

Thiazolidinediones
Thiazolidinediones predominantly affect liver, skeletal muscle,
and adipose tissue.
1)In the liver: decrease glucose output and insulin levels.
2)In muscle: increase glucose uptake.
3)In adipose tissue: increase glucose uptake and decrease
fatty acid release and may increase the release of hormones
such as adiponectin and resistin.

Thiazolidinediones…
•The actions of these drugs require the presence of insulin.
•Thiazolidinediones
–reduce plasma glucose and triglycerides
–do not cause hypoglycemia
–are associated with exacerbating or causing congestive
heart failure
–Include: pioglitazone, rosiglitazone

100

Thiazolidinediones…..

Absorption, metabolism & elimination
•They are readily absorbed from the GIT
• rapidly metabolized by the liver
•Plasma elimination half-life is
–2-3hrs for rosiglitazone
–slightly longer for pioglitazone
•About two thirds of conjugated metabolites appear in the
urine and the remainder in the feces

Thiazolidinediones…

ADR
–less hypoglycemia than sulfonylureas
–C/I in CHF (NYHA II, III) & liver disease
–can also cause mild anemia & weight gain
–fractures in females
–Troglitazone, the first medication in this class, was
withdrawn because of cases of fatal liver failure
–Safety in pregnancy is not established

Glucosidase Inhibitors
•glucosidase inhibitors primarily act to decrease postprandial
hyperglycemia
– by slowing the rate at which carbohydrates are absorbed
from the gastrointestinal tract
• They act by competitively inhibiting glucosidases
–a group of enzymes in the intestinal brush border
epithelial cells (glycoamylase, sucrase, maltase, and
dextranase)
•Include: acarbose, miglitol

Glucosidase Inhibitors….
Side effects
•Gastrointestinal disturbances
– (loose stools, flatulence,and abdominal cramping)
•Unlike the sulfonylureas, insulin, and the glitazones, glucosidase
inhibitors do not cause weight gain
•Insulin levels do not change in the presence of glucosidase
inhibitors
–so fasting hypoglycemia does not occur

Incretins
•Gut hormones that amplify postprandial insulin secretion
–glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP)
•Therapeutic drugs in this class include
–GLP-1 receptor agonists
–Dipeptidyl peptidase 4 (DPP-4) inhibitors, which increase
levels of both GLP-1 and GIP

Incretins…

•GLP-1
–released from the enteroendocrine L-cells of the gut
– inhibits glucagon secretion and enhances glucose-
dependent release of insulin
– activity is enhanced by inhibiting its rapid inactivation
•Inhibiting dipeptidyl peptidase IV & endopeptidase

Incretins…

•When GLP-1 is infused in patients with type 2 diabetes,
–it stimulates insulin secretion and lowers glucose levels
–It is rapidly proteolyzed & cleared rapidly by the kidney
–As a result, the half-life of GLP-1 is only 1 to 2 minutes
–The native peptide, therefore, cannot be used
therapeutically

GLP-1 Receptor Agonists..
•Incretin mimetics (Sc injections) (GLP-1 Receptor
Agonists)
Exenatide
Liraglutide
Albiglutide
Dulaglutide
•Actions
–decrease glucagon secretion
–slow gastric emptying
–reduce food intake, and
–promote β-cell proliferation.
108

109
Action of drugs affecting GLP-1

GLP-1 Receptor Agonists..
•ADRs
–may increase the risk of pancreatitis
–cases of renal impairment and acute renal injury have been
reported in patients taking exenatide
–GI disturbance (NVD)
–both exenatide and liraglutide stimulate thyroidal C-cell
(parafollicular) tumors in rodents

110

DPP-4 Inhibitors (orally)

•inhibition of the enzyme DPP-4 prolongs of the action of
endogenously released GLP-1 and GIP
–Sitagliptin
–Saxagliptin (dosage adjustment in renal disease and
concurrent use of strong CYP3A4/5 inhibitors)
–Vildagliptin (rarely, it can cause hepatitis)
–Alogliptin (hypersensitivity reactions)
–Linagliptin (no dosage adjustment is in renal failure)

Na-glucose cotransporter 2
inhibitors (orally)
•SGLT-2 inhibitors block the re-uptake of glucose in the
renal tubules, promoting loss of glucose in the urine
•This causes both mild weight loss, and a mild reduction in
blood sugar levels with little risk of hypoglycemia
•Examples of SGLT-2 inhibitors include:
–Canagliflozin
–Dapagliflozin
–Empagliflozin

Na-glucose cotransporter 2
inhibitors
•ADR
–Genital and urinary tract infections
–polyuria, pruritus, thirst, osmotic diuresis,
constipation
•C/I: renal disease
113

Other hypoglycemic drugs
Pramlintide
• is a synthetic analog of islet amyloid polypeptide (IAPP) that
when given subcutaneously
–delays gastric emptying
–suppresses glucagon secretion, and
–decreases appetite
•It is approved for use both in type 1 and insulin-treated type
2 patients

Components of comprehensive
diabetes care

PHARMACOLOGY OF CNS DRUGS

1

Introduction to CNS Pharmacology

2

CNS pathways
A . Excitatory Pathways
1.Opening of Na channels (influx of Na
+
)
2. Depressed Cl
-
influx or K
+
efflux or both
3.Changes in internal metabolism of the postsynaptic
neuron to excite cell activity by
by increasing excitatory membrane receptors or
 decrease inhibitory membrane receptors

3

CNS pathways
B . Inhibitory Pathways
1.Opening of Cl
-
channels (Influx of Cl
-
ion )
2.Increase conductance of K
+
ions (efflux of K
+
)
3.Activation of enzymes which inhibit cellular metabolic
functions & increase inhibitory synaptic receptors or
decrease excitatory receptors

4

5

6
•Excitatory neurons – EPSP-increases the probability of
generating an action potential.
•Inhibitory neurons – IPSP-decrease the probability of
generating an action potential.
•There is always interaction b/n these neurons
•The level of electrical activities determine the state of the
patient - seizure, anxiety, …..…..etc

7
The basic processes of synaptic transmission in the CNS are
essentially similar to those operating in the periphery.
–The release of neurotransmitters (NTs) & receptor binding
–Recognition of the NT by membrane receptors triggers IC
changes
–NT release regulation (presynaptic receptors);
But major differences are;
More than 10 NT in the CNS
There are inhibitory and excitatory NT in the CNS
CNS is much more complex than PNS

8
NTs in the CNS
Can be inhibitory or excitatory
Inhibitory: GABA, Glycine
Excitatory: Glutamate, Aspartate, Ach, NE, DA, 5-HT
Others
•Neuro-peptides (e.g. sub-P, enkephalins)
•Purine nucleotides (adenosine, ATP)

9 Summary of NT of the CNS.

10
Sites of drug action which can alter synaptic transmission
1.AP in presynaptic fiber
2.Synthesis
3.Storage
4.Metabolism
5.Release
6. reuptake
7.degradation
8.binding site of NT
9.Receptor-induced increase or
decrease in ionic conductance

11
Classification of drugs acting on CNS
•Sedative - hypnotics
•Anti Epileptics
•Anti PD
•Antipsychotics /Neuroleptics
•Anesthetics (local & General)
•Antidepressants
•Analgesics

12
SEDATIVE HYPNOTICS
Amnesia
sedation
Hypnosis
Coma
Death
Awake

SEDATIVE HYPNOTICS
•A sedative( anxiolytic) drug decreases activity, moderates
excitement, and calms the recipient, whereas
•a hypnotic drug produces drowsiness and facilitates the
onset and maintenance of a state of sleep that resembles
natural sleep and from which the recipient can be aroused
easily.

13

Sedative / hypnotics ….
A. Effective sedative
– Reduces anxiety without inducing sleep
– Slight decrease on motor activity
– CNS depression should be minimal
– Quicker onset, shorter duration, steeper dose
response curve
14

15
B. Effective Hypnotic
• produce drowsiness
•encourage the onset and maintenance of a state of sleep
• pronounced depression of CNS
• Graded dose-dependent depression of CNS function is
a characteristic of most sedative-hypnotics

Sedative Hypnotics

16
•Hypnotics
at lower dose may act as sedative and
at higher dose can produce general
anesthesia
Sedative Hypnotics
Sedation hypnosis general anesthesia comma

17

18
Classification of sedative-hypnotics
1.Barbiturates (ultra, short and long action)
2.Benzodiazepines (short, intermediate & long)
3.New sedative/hypnotics
4.Other drugs

Barbiturates
•Potentiate GABA action on chloride entry into the neuron by
prolonging the duration of the chloride channel openings
•Classified by duration of action
–Ultra short-acting (Thiopental Na) =<20 min duration
–Short-acting (Secobarbital, pentobarbital) - 3 - 4 hrs
–Intermediate-acting (Amobarbital, aprobarbital &
butabarbital) - 6- 8 hrs
–Long-acting (Phenobarbital, mephobarbital) - 10 - 16 hrs

20

CNS NTs

Barbiturates action
•Depression of CNS
–At low doses - Produce sedation (calming effect, reducing
excitement)
–At higher doses - Hypnosis, followed by anesthesia (loss of
feeling or sensation), and finally, coma and death
–No analgesic properties - May even exacerbate pain
–Chronic use leads to tolerance
•Respiratory depression
–Suppress hypoxic and chemoreceptor response to CO
2
•Enzyme inducers - ↓ Action of other drugs

Barbiturates cont…
Therapeutic uses
•Anesthesia: Thiopental are used IV
•Anticonvulsant: Phenobarbital
–Tonic-clonic seizures, status epilepticus, and eclampsia
–DOC for treatment of young children with recurrent febrile
seizures
–Can depress cognitive performance in children - cautiously
•Anxiety -
Mild sedatives for anxiety, nervous tension and insomnia
–As hypnotics, they suppress REM sleep
•Most have been replaced by the benzodiazepines

Barbiturates cont…
Adverse effects
•Drowsiness, impaired concentration, mental and physical
sluggishness (depressant effects synergize with ethanol)
•Drug hangover, nausea, dizziness
•Physical dependence: Abrupt withdrawal cause tremors,
anxiety, weakness, restlessness, nausea and vomiting, seizures,
delirium, and cardiac arrest
–Withdrawal is much more severe than that associated with
opiates and can result in death
•Drug Interactions- other depressants, oral contraceptives, etc

Benzodiazepines
•Potentiate effect of GABA by ↑ the frequency of Cl channel
opening
•Classifications
–Short acting agents - Triazolam
–Intermediate acting agents - Alprazolam, Lorazepam,
Oxazepam, Temazepam, Chlordiazepoxide
–Long acting agents - Diazepam, Flurazepam

Benzodiazepines action:
•Reduction of anxiety - At low doses
•Sedative and hypnotic actions: All have some sedative
properties and some produce hypnosis at higher doses
•Anterograde amnesia - Temporary impairment of memory
–Impairs a person's ability to learn and form new memories
•Anticonvulsant: Several of the benzodiazepines
–Some are used to treat status epilepticus and other seizure
disorders
•Muscle relaxant: At high doses

Benzodiazepines
•Gained popularity over barbiturates because
BZPs have a high therapeutic index
Hypnotic doses do not affect respiration & CVS functions
 slight effect on rapid eye movement phase of sleep, hence
there is no hangover
Produce less physical dependence
 do not alter the disposition of other drugs by microsomal
enzyme induction
Presence of BZD antagonist (flumazenil) as antidote
26

Benzodiazepines …
•Therapeutic uses
–Anxiety disorders
–Muscular disorders: Muscle spasms - Diazepam
–Amnesia – Short acting ones
–Seizures – Clonazepam, diazepam and lorazepam
–Sleep disorders – Flurazepam, temazepam, triazolam

Benzodiazepines …
•Adverse effects
–Drowsiness, confusion, ataxia, cognitive impairment,
tolerance, dependence (Psychological and physical
dependence) and withdrawal symptoms
•Precautions
– Avoid in pregnancy
–Liver disease, acute narrow-angle glaucoma.
–Alcohol and other CNS depressants
–Less dangerous than older anxiolytic and hypnotic drugs

29
BZD antagonist / flumazenil
Anxiogenic and proconvulsant
Use
In case of BZD over dosage
(if only respiration severely depressed)
 also blocks effect of zolpidem, zeleplon (hypnotic acts
similarly to BZDs) but more dose is required (5mg)
 To reverse BZD anaesthesia and allows early discharge of
patients and easy for post anesthetic management

30
Flumazenil has fast on set (sec
s) and short duration of action
(1-2 hrs)
BZDs have longer duration of action
Therefore, repeated administration of flumazenil is needed

BZD antagonist / flumazenil

3. Newer sedative hypnotics
Non BZD sedatives: agonist for a subtype of BZD receptor
Zopicolone, eszopiclone, Zolpidem & Zaleplon,
Ramelteon, a melatonin receptor agonist
 Buspirone

31

Benzodiazepine – like drugs
•zolpidem, zaleplon, and eszopiclone
•not benzodiazepines but appear to exert their CNS effects via
interaction with certain benzodiazepine receptors,
•In contrast to BZPs, these drugs bind more selectively,
interacting only with GABA
A receptor
•Their CNS depressant effects can be antagonized by flumazenil.
32

Benzodiazepine – like drugs
•efficacies similar to those of the hypnotic
benzodiazepines
•Favorable clinical features, rapid onset of activity and
modest day-after psychomotor depression with few
amnestic effects
•Zaleplon acts rapidly and short DOA-management of
patients who awaken early in the sleep cycle
•bind more selectively because these drugs interact only
with GABA
A-receptor isoforms that contain α
1 subunits.

33

Ramelteon
•Melatonin receptors are thought to be involved in
maintaining circadian rhythms underlying the sleep-wake
cycle
•prescribed specifically for patients who have difficulty in
falling asleep
•reduced the latency of persistent sleep with no effects on
sleep architecture and no rebound insomnia or significant
withdrawal symptoms
34

35
Buspirone
Partial agonist at serotonin receptor (5-HT 1A receptor)
Also binds to brain dopamine receptor (D
2 )
Less Psychomotor impairment than benzodiazepines
Selective with minimal depressant effects on the CNS
Less effective in panic disorders /acute anxiety states b/c of slow
onset of action (effects take days or weeks to develop)
Relief anxiety without causing marked sedative, hypnotic, or euphoric
effects
Minimal abuse liability & no anticonvulsant or muscle relaxant
properties (unlike BZDs)
No rebound anxiety/withdrawal signs on abrupt discontinuance

36
Pharmacokinetics
Rapidly absorbed
T1/2 2 to 4 hrs
Rifampin decrease half life
Erythromycin increase half life
Side effects
•dizziness, nausea, headache, but not sedation or loss of
coordination
•less troublesome than with benzodiazepines
•Increase BP with MAO inhibitors
Buspirone

37

ANTIPARKINSONIAN DRUGS

38
Parkinson’s disease (PD)
• is disorder of mov’t that occurs mainly in the elderly
•Occurs for a variety of possible reasons
–Exposure to certain toxins (manganese dust, CS2)
–Drug induced parkinsonism : reserpine, chlorpromazine,
haloperidol & other antipsychotics that block D
2
–Post encephalitic parkinsonism : after viral infection
– Idiopathic parkinsonism : unknown cause

39
•The basal ganglia are responsible for controlling automatic
movements of the body by the action of dopamine (DA)
•Degeneration of basal ganglia in the deeper grey matter of the
brain (substantia nigra) causes PD.
•DA level in the brain’s substantia nigra normally fall with ageing
•The level has to fall to one-fifth of normal values for signs of PD
to emerge
•In PD, there is extensive destruction of dopaminergic neurons
of SN (DA deficiency)
Pathophysiology of PD

40

Strategy of Treatment
•Symptoms of Parkinson's reflect
– imbalance b/n the excitatory cholinergic neuron & the
greatly diminished number of inhibitory dopaminergic
neurons.
•Therapy is aimed
–to restore the dopamine in the basal ganglia & antagonizing
the excitatory effects of cholinergic neurons.
–Thus re-establishing the correct dopamine and -Ach
balance.

41

42

Cardinal Features
Brady kinesis(slowness in initiating & carrying out voluntary
mov’t)
Muscular rigidity
Resting tremor
Impaired postural balance
Pathologic Hallmark
Loss of pigmented, dopaminergic neurons in substantia nigra
pars compacta
Intacellular inclusions: Lewy bodies

43

44
Parkinsonism (PD) –
signs

Overview of Drug Therapy
Therapeutic Goal
To improve ability for activities of daily life (only symptom
relief)
Treatment Strategy
Restore balance between DA and ACh by activating DA
receptors or blocking ACh receptors
Overview of Drugs Employe
Two major categories (dopaminergic & anticholinergic
drugs).

45

46
Classification of drugs
1. Drugs affecting brain dopaminergic system
a.Dopamine precursors: levodopa
b. Peripheral decarboxylase inhibitors: carbidopa & benserazide
c.Dopaminergic agonists: bromocriptine, lisuride, pergolide,
ropinirole, cabergoline & pramipexole
d. MAO-B inhibitors : Selegiline
e.COMT inhibitors: Entacapone, tolcapone
f.Dopamine facilitator : Amantidine

47
2.Drugs affecting brain cholinergic system
a.Anticholinergcs: Benzatropine, Trihexyphenidyl
(benzhexol), Procyclidine, biperiden
b.Antihistaminics: promethazine
3.Neural transplantation (on experimental phase)

48
Levodopa (L-DOPA)
•first-line treatment for PD
•is the immediate metabolic precursor of dopamine
–Prodrug for DA
–Levodopa can cross BBB while DA does not

49
Pharmacokinetics
•Levodopa is rapidly absorbed from the small intestine
•Food delays absorption of the drug
– should be taken 30–60 minutes before meals
•More than 95% of oral dose is decarbxylated in periphery tissue
mainly in gut & liver
–DA in periphery thus acts on peripheral organs & may
cause unwanted effects. It also acts on CTZ
•Therefore, peripheral dopa decarboxylase inhibitor (carbidopa
or benserazide) reduce Levodopa metabolism in periphery
Levodopa

Synthesis of dopamine from levodopa in the absence and
presence of carbidopa

50

51
Levodopa

52
Pharmacodynamics
The benefits of levodopa treatment begin to diminish after about
3 or 4 years of therapy regardless of the initial therapeutic
response.
•Initial effective doses may fail to produce therapeutic benefit &
responsiveness to levodopa may be lost completely. Possibly
due to
–The disappearance of dopaminergic nigrostriatal nerve
(disease progresses beyond ability of L-dopa to control it.)
– Some pathologic process directly involving the striatal
dopamine receptors like tolerance.
Levodopa

53
•Early initiation lowers mortality rate but does not stop the
progression
•Long term therapy associated with number of adverse
effects
•The most appropriate time to introduce levodopa therapy
must be determined individually
Levodopa

54
Two main adverse effects after prolonged therapy
• Dyskinesia (involuntary writhing movements)
–Happened to 80% of patients receiving levodopa therapy for long
periods
–The margin between the beneficial & the dyskinetic effect becomes
progressively narrow
•On / off phenomenon
–Fluctuations in clinical response with increasing frequency as
treatment continues
–Patient's motor state may fluctuate dramatically with each dose of
levodopa
Levodopa

55
•On / off phenomenon
–Each dose of levodopa
•Effectively improves mobility for few hours with marked
dyskinesia (
on - period)
•Marked rigidity & akinesia return rapidly at the end of the dosing
interval (off - period) - wearing off
–Most common on late stage of PD
–'on-off' effect is not seen in untreated PD patients or with other
anti-PD drugs
–Apomorphine may provide temporary benefit for patients with
severe off-periods who are unresponsive to other measures

56
The possible reason for on/off effect
As the disease advances
The ability of neurons to store dopamine is lost
The therapeutic benefit of levodopa depends on the continuous
formation of extraneuronal dopamine
Continuous supply of levodoapa is required otherwise the on/off
phenomenon will occur
Strategies to manage:
Infusion, sustained release, or multiple short interval doses
of L-Dopa
Add selegiline to prevent metabolism by MAO-B.
Use receptor agonists

57
Other adverse effects
•Nausea & anorexia
–Occurs at initial therapy & tolerance gradually develops (dose can
be progressively increased )
–Antiemetics : domperidone (DA antagonist on CTZ )
•Postural hypotension, cardiac arrthymias & excerbation of angina
– Due to β adrenergic action of peripherally formed DA
–More sever for patients with pre existing heart diseases
•Psychological effects:
schizophrenia-like syndrome
–C/I to psychotic patients

58
Drug Interactions
•Pharmacologic doses of vit B
6 enhance extracerebral
metabolism of levodopa as pyridoxin (vit B
6) is cofactor for
DOPA decarboxylase
•Phenothiazines, butyrophenones & metoclopramide block
DA receptors
•Nonselective MAO inhibitors prevent degradation of
peripherally synthesized DA & NA --- hypertensive crisis can
occur
–Levodopa should not be given to patients taking MAO- A
inhibitors or within 2 weeks of their discontinuance

59
Dopamine receptor agonists
Unlike levodopa, DA receptor agonists
•Lower incidence of on /off phenomenon & dyskinesias
•Do not require enzymatic conversion to active metabolite
•No DA toxic metabolites
– Do not have oxidative stress induced dopaminergic neural damage
•Selectively affect certain DA receptors
•Used for patients who have largely lost the capacity to synthesis, store
& release dopamine from levodopa
•Have longer duration of action than that of levodopa

60
Act directly on postsynaptic DA receptor types (primarily
D
2)
Effective as monotherapy or as adjuncts to carbidopa
/levodopa therapy

Dopamine receptor agonists

61
DA receptor agonists available for treatment of PD
Bromocriptine (Ergot derivative)
–Potent D
2 agonist & partial D
1 agonist
–High dose is needed if used alone
–Used only in late case as supplement to levodopa
–Also used for treatment of hyperprolactinemia (reduce
prolactine release) in lower doses than for PD
•gynecomastia

62
Pergolide
Ergot derivative
Agonist of both classes (D
1 & D
2)
More effective than bromocriptine in relieving the
symptoms & signs of PD
Increase "on-time" among response fluctuators
Allow the levodopa dose to be reduced

DA receptor agonists

63
Pramipexole
• Nonergoline derivative
•Selective activity at D
2 class (D
2 & D
3 receptors)
–little or no activity at D
1
• Effective when used as monotherapy for mild parkinsonism
•Also helpful in patients with advanced disease
– permitting dose of levodopa to be reduced & smoothing out
response fluctuations
•Scavenge hydrogen peroxide /neuroprotective effect/
DA receptor agonists

64
Ropinirole
•Nonergoline derivative
•Relatively pure D
2 receptor agonist
•Effective as monotherapy in patients with mild PD
•Used as a means to smoothen the response to levodopa in
patients with more advanced disease & response fluctuations
•Metabolized by CYP1A2
–drugs metabolized by CYP1A2 may significantly reduce
clearance of ropinirole
DA receptor agonists

65
•Initial t/t with bromocriptine or pergolide (non selective agonists)
–may cause hypotension
–induce nausea & fatigue
• Symptoms are transient & require slow upward adjustment of
the dose over a period of weeks to months
•Selective agonists (pramipexole & ropinirol) are well tolerated
–Can be initiated more quickly
–Therapeutic doses can be achieved in a week or less than a
week
DA receptor agonists

66
Adverse effects of DA agonists
GIT effects
•Anorexia , nausea & vomiting : can be minimized by taking the
medication with meals
•Constipation, dyspepsia, & symptoms of reflux esophagitis
may also occur
CVS effects
•Postural hypotension at the initiation of therapy
•Cardiac arrhythmias an indication for discontinuing treatment
•Cardiac valvulopathy may occur with pergolide

67
Dyskinesias
•Abnormal movements similar to those produced by levodopa
–Can be reversed by reducing the total dose of the drug
Mental disturbances
•Confusion, hallucinations, delusions & other psychiatric
reactions
•More common & severe with DA receptor agonists than with
levodopa
•They clear on withdrawal of the medication
Adverse effects of DA agonists

68
C/I
•DA agonists are C/I in patients with
–History of psychotic illness
–Recent myocardial infarction
–Active peptic ulceration
• Patients with peripheral vascular disease should avoid
taking ergot-derived agonists
DA receptor agonists

69
MAO-B inhibitors
MAO-B : The predominant form of MAO in the striatum & responsible
for most of oxidative metabolism of DA in the brain
Selegiline (deprenyl)
•At low to moderate doses ( < 10mg/day), it is selective & irreversible MAO-B inhibitor
– It does not metabolize peripheral catecholamine
–At dose > 10mg/day , MAO-A can be inhibited
•Used as adjunctive therapy for patients with declining or fluctuating
response to levodopa

70
↓ free radical generation
from DA metabolites
↓oxidative stress
Neuroprotective effect ( ?)
MAO-B Inhibitor
Reduce DA metabolism ↑DA concentration
in striatum
-Allow levodopa dose reduction
-May reduce on / off phenomena
Enhance action of
levodopa

71
COMT inhibitors
–Tolcapone & Entacapone
•Addition of COMT inhibitors to carbidopa / levodopa
combination delays ’’wear off’’ phenomenon

72
Levodopa
3-OMD

Tolcapone
Entacapone

(-)
Blood brain barrier
Levodopa
3-OMD
Dopamine
Dopamine
3-MT DOPAC
COMT
DDC
Carbidopa
Benserazid

(-)
Tolcapone
COMT
(-)
DDC
COMT

Tolcapone

HVA
MAO-B
MAO-B
COMT (-)

Selegiline

(-)
(-)
OMD,O-methyldopa
DDC, dopadecarboxylase
HVA,homovanilic acid
MT,methoxytyramine
DOPAC,dihydroxy phenylacetic acid
COMT, catechol-o-methyl transferase
MAO-B, Monoamine oxidase B

Brain Periphery

73
Tolcapone
•Has long duration of action
•Inhibit both central & peripheral COMT
• Associated with hepatotoxicity
–Should be used with appropriate monitoring for hepatic injury
only when other therapies are not effective
Entacapone
• Has short duration of action
• Act peripherally
COMT Inhibitors

74
Amantadine
•Antiviral agent with several pharmacological effects
•MoA for its anti PD activity is not clear, possibly by
–Facilitating synthesis, release or reuptake of DA in the
striatum
–Its anticholinergic properties
–Blocking NMDA glutamate receptors

75
Muscarinic receptor antagonists
•Drugs with higher central to peripheral anticholinergic ratio
than atropine but they have similar pharmacological profile
•Reduce the unbalanced cholinergic activity in striatum
•The only drugs effective in drug (phenothiazine) induced
parkinsonism
•Treatment has to start from small dose & gradually increased
until benefit occurs or side effects limit further increment

76
•Benzatropine (muscarinic receptor antagonist) used for
parkinsonism caused by antipsychotic drugs
•Other antimuscarnic agents: Biperiden, orphenadrine,
procyclidine, trihexyphenidyl
•Side effect profile is similar to atropine
–Dryness of mouth, nausea, constipation, palpitation, cardiac
arthymias, confusion, agitation, restlessness, mydriasis,
increased intraocular pressure, defective accommodation

Muscarinic receptor antagonists

77
DRUG TREATMENT OF PSYCHIATRIC
DISORDERS

Nature of Psychosis & Schizophrenia
•The term "psychosis" denotes a variety of mental disorders:
–delusions (false beliefs), hallucinations, and
disorganized thinking.
•Schizophrenia is a chronic psychotic illness characterized
by
• Disordered thinking and
• Reduced ability to comprehend reality.

78

Schizophrenia
Etiology & Pathogenesis
•Although there is strong evidence that schizophrenia has a
biologic basis, the exact etiology is unknown.
1.Genetic & Environmental factors
•Number of susceptibility genes are identified w/c show
strong but incomplete hereditary tendency
•Some environmental factors have been identified as
possible predisposing factors (E.g. maternal virus
infections)

79

Etiology & Pathogenesis …
2.Neurochemical theories
•A change in amine NTs especially DA has been proposed
as a cause of psychosis.
•The main neurochemical theories centre on DA &
glutamate
•However, 5-HT & other NTs might also involve

80

Etiology & Pathogenesis …
3. Anatomic damage
 In psychotics brain, there are certain areas w/c gets atrophied
•Computed Tomography (CT) scan and MRI studies reveal
Enlarged ventricles
Suggest deterioration or atrophy of brain tissue
•Positron emission tomography (PET) scans
Suggest atrophy in the prefrontal areas

81

82
Main clinical features
 Positive symptoms : delusions, hallucinations & thought
disorder
– Thought to be occurred in the mesolimbic pathway
• Commonly occur in acute phase of the illness
• Usually respond to antipsychotic drug therapy
 Negative symptoms: apathy, social withdrawal &
lack of drive
– Thought to be occurred in the mesocortical pathway
• Occur in the chronic phase of illness
•Tend to be resistant to dug therapy

Classification of Antipsychotic Drugs
•Can be classified by potency, generation or chemical structure.
•From a clinical view point, classification by potency is more
helpful.
Classification by potency;
• Conventional antipsychotic agents can be classified as low
potency, medium potency, or high potency

83

84

Antipsychotic Drugs: Relative Potency and Incidence of Side Effects
Incidence of Side Effects

Drug
Equivalent
oral dose
(mg)
Extrapyramidal
effects
Sedation Orthostatic
hypotension
Anticholinergic
effects
Conventional
agents
Low potency
Chlorpromazine
Thioridazine
Moderate potency
Triflupromazine
Perphenazine
Loxapine
High potency
Haloperidol
Fluphenazine

100
100

25
10
10

2
2

Moderate
Low

Moderate
Moderate
Moderate

High
High

High
High

High
Moderate
Moderate

Low
Low

High
High

Moderate
Low
Low

Low
Low

Moderate
High

Moderate
Low
Low

Low
Low
Atypical Agents
Clozapine
Risperidone
quetiapine

50
4

Very low
Very low

High
Low

Moderate
Low

High
None

85
Broad category of antipschotic drugs
1
st
generation ('typical') & 2
nd
generation ('atypical')
No clear distinction b/n them ; however, grouping is based
on
–Receptor profile
–Incidence of extrapyramidal side effects (less in atypical
group)
–Efficacy in 'treatment-resistant' patients
–Efficacy against negative symptoms

Typical antipsychotics:
•Tend to produce Extrapyramidal side effects:
Parkinsonism – tremors, rigidity, slowness of movement,
temporary paralysis
Dystonia – involuntary muscle contractions
Akathisia – inability to resist urge to move
Tardive dyskinesia – involuntary movements of the mouth,
lips, and tongue ,Chewing, grimacing, etc.

86

Atypical antipsychotics :
do not induce EPSE
Block D2 receptors and 5-HT receptors
As opposed to typicals, these are more loosely bound to
D2 receptors
Easier dissociation
 the higher occupation of D2 receptors by drug, the
higher incidence of EPSE

87

88
Summary of neuroleptic agents.

89
Depot antipsychotics
Estrefication of the antipsychotic with long chain fatty
acid
The drug will be released at constant rate for long time
Reduce compliance problem
However reduced flexibility of dosage, pain at site of
administration, high incidence of EPS & weight gain are
its drawbacks
Some antipsychotic available as Depot: Haloperidol,
Flupenthixol, Zulcopenthioxol, Fluphenazine, pipothiazine

90
Mechanism of Action
•All effective antipsychotic drugs block D
2 receptors
•The degree of blockade on different receptors considerably varies
Chlorpromazine: α
1 > 5-HT
2A > D
2 > D
1
Haloperidole: D
2 > α
1 > D
4 > 5-HT
2A> D
1>H
1
Clozapine: D
4 = α
1 > 5-HT
2A> D1=D
2
Aripiprazole: D
2= 5-HT
2A >D
4 > α
1 = H
1 >>D
1
Olanzapine: 5-HT
2A >H
1>D
4>D
2> α
1 = H
1>>D
1
•Antipsychotic action has shown good correlation with the capacity
to bind to D
2 receptor
•There is no clear correlation with antipsychotic activity & the
capacity to bind with D
1, D
3, & D
4
•Activities on other NT receptors may determine side effect profile

91
Pharmacological Action
1.ANS
Varying degree of α adrenergic blocking activity
More potent drugs have lesser α blocking activity
Anticholinergic property is generally weak
2. Local anesthetic
CPZ is potent LA as procaine however it causes irritation
3.CVS
Antipsychotics produce postural hypotension by central &
peripheral action on sympathomimetic tone
4. Endocrine effects
Increase prolactine secretion by blocking the inhibitory effect of
DA
•Galactorrhoea, gynaecomastia
increased libido (women), decreased libido (men)

92
Use of Antipsychotics
1.Schizophrenia
2.Anxiety
Should not be used for simple anxiety b/c of autonomic & EPS
BZD
S are preferable; however, those not responding or having
psychiatric base for anxiety may be treated with neuroleptics.
3. As antiemetics
Control wide range of drug & disease induced vomiting at dose
much lower than those needed for psychosis but ineffective in
motion sickness
4. Other uses
Potentiate hypnotics, analgesics, & anasthetics
Intractable hiccough may respond to parentral CPZ
In tetanus, CPZ is used achieve skeletal muscle relaxation

93
Adverse Effects
I. Dose related toxicity
1.CNS : Drowsiness, lethargy, mental confusion, Increased
appetite & weight gain (not with haloperidol)
2.CVS: Postural hypotension, Palpitation
3.Anticholinergic: Dry mouth, blurred vision
4.Endocrine: Hyperprolactinemia
Atypical antipsychotics don’t raise prolactin level

94
2.Extrapyramidal disturbances (EPS)
Pseudo parkinsonism
Rigidity, tremor, hypokinesia, mask like face
Appears within 1- 4 weeks of therapy & persist unless dose is
reduced
Anti PD drugs can be given together with antipsychotics
Acute muscular dystonias
Muscle spasm mostly in linguo-facial muscles
More common in children bellow 10 & in girls
Occurs with in a few hrs of single dose or at 1
st
week of therapy
i.m injection of central anticholinergic (promethazine or
hydroxyzine) can clear the reaction with in 10 – 15 minutes

95
Akathisia
Restlessness, feeling discomfort, agitation as a complete
desire to move about with out anxiety
Occurs with in 1-8 weeks of therapy & misleads as
‘exacerbation of psychosis’
No specific antidote available
Central anticholinergic may reduce the intensity but
propranolol is more effective
Addition of diazepam may also be used
However, most cases of akathisia require dose reduction
or alternative antipsychotic

96
Malignant neuroleptic syndrome
Rarely occurs with potent antipsychotics
Patient develops marked rigidity, immobility, tremor, fever, semi
consciousness, fluctuating BP & HR
Lasts 5 – 10 days after withdrawal & may be fatal
Anticholonergics are of no help rather large dose of bromocriptine may be
useful
Tardive dyskinesia
Manifests as purposeless involuntary facial & limb movements like constant
chewing, puffing of cheeks & lip licking
More common in elderly women
May subside months or yrs after withdrawal of the t/t or may be life long
No satisfactory solution found

97
II.Hypersensitivity
1.Cholestatic jaundice
2.Skin rash, urticaria, contact dermatitis ,
photosensitivity ( more common with CPZ)
3.Agranulocytosis, rarely, ( more common with
clozapine)
4.Myocarditis

98
Drug Interaction
1.Neuroleptics potentaite all CNS depresant:- Hypnotics,
anxiolytics, alcohol, opioids, antihistamines & analgesics
2.Neuroleptics block the action of levodopa & DA agonists
in parkinsonism
3.Antihypertensive effect of clonidine & methyldopa is
reduced
4.They are poor enzyme inducers

99
Drugs of Choice
•Individual patients differ in their response to d/t antipsychotics
•There is no way to predict w/c patient will respond better to
w/c drug
•However drug selection should consider state of the patient &
side effect profile of the drug
If the patient is aggressive, sedating drugs such as CPZ would be
drug of choice
Haloperidol is drug of choice if postural hypotension is a problem
If there is difficulty in frequent administering of the drug go for
depot antipsychotic drugs

100
Summary of drug therapy for schizophrenia
A. Emergency phase
First line: Haloperidol, 5-10 mg I.M./I.V. over 30-60 minutes.
Daily dose may go as high as 40 mg.
Alternative: Chlorpromazine hydrochloride, 25 mg, I.M. and
raise to 200 mg QD for acute attacks
B. Stabilization phase
First line
Haloperidol, 1-15 mg/day P.O.
Alternative
Chlorpromazine, 75- 300 mg/ P.O. QD in divided doses.

C. Maintenance (chronic therapy)
First line
Haloperidol, 1-15 mg/day P.O.
Alternatives
Chlorpromazine, 75- 300 mg/day P.O. QD. in divided doses.
OR
Fluphenazine decanoate, 12.5-100 mg IM every 3-4 weeks

Dosage forms: Injection, (Depot, Oily), 25mg/ml in 1ml
ampoules
N.B.
After 6 months in remission the drug can be withdrawn for a trial
period to see if relapse occurs, at which point therapy is
instituted.

101

Antiepileptic Drugs
102

Seizure
•refers to a transient alteration of behavior due to the
disordered, synchronous, and rhythmic firing of populations of
brain neurons
Epilepsy
refers to a disorder of brain function characterized by the
periodic and unpredictable occurrence of seizures
Seizures can be "non-epileptic" when evoked in a normal brain
by treatments such as electroshock or chemical convulsants or
It is "epileptic" when occurring without evident provocation
103

Epileptic seizure classification
104

•Partial seizures
begins focally in a cortical site
Simple-partial seizure
No loss of consciousness
May have muscle twitching or sensory hallucinations
Complex-partial seizure
Impaired consciousness
With confusion and post seizure amnesia
105

Generalized Seizures
•Involves both hemispheres of the brain, not one specific
location
•Types:
Tonic
–body becomes rigid, lasts a minute or less
Clonic
Initiated with muscle jerks, and may be accompanied by
shallow breathing, loss of bladder control, and excess
salivation
106

Myoclonic
–Occurs with sudden, massive, brief muscle jerks or non-
massive, quick jerks
–Consciousness is not lost
–Can occur during sleep
Atonic
–Begins with sudden loss of muscle tone and consciousness
–Muscles relax, limbs go limp (weak)
–Lasts a few seconds to a minute, then patient can resume
standing and walking

107

 Absence
–It causes interruption of activities by:
Blank stare (absence of fixed looking)
Rotating eyes
Uncontrolled facial movements
Rapid eye blinking, and/or jerking of an arm or leg
–No generalized convulsions
–Usually lasts 30 seconds or less
–Many times it progresses to tonic-clonic as the patient gets
older

108

Status epileptics
–Continuous tonic-clonic seizures with or without return to
consciousness
–High fever and lack of oxygen severe enough to cause brain
damage or death

109

Pathophysiology of Seizures
Increased EAA
•Increased EAA Transmission
•Increased sensitivity to EAA
•Progressive increase in
glutamate release
•Increased glutamate and
aspartate at start of seizure
•Up regulation of NMDA
receptors
Decreased GABA
•Decreased binding of GABA
and benzodiazepines
•Decreased Cl
-
currents in
response to GABA
•Decreased glutamate
decarboxylase activity
•Interfere with GABA
110

•Strategies in treatment of epilepsy
–Stabilize membrane and prevent depolarization by action on
ion channels
–Increase GABAergic transmission
–Decrease EAA transmission
Types of Treatment
–Medication
–Surgery
–Nonpharmacologic treatment
•Ketogenic diet
•Vagus nerve stimulation
•Lifestyle modifications
111

Antiseizure /antiepileptic drugs
•Class of drugs for epilepsy
–Type I antiepileptics - Inhibit Na+ channels
•Phenytoin, Carbamazepine, lamotrigine, felbamate, oxycarbazepine
–Type II antiepileptics – Multiple action
•Inhibit Ca++ or Na+ channels or promote GABA activity
•Valporic acid, benzodiazepines, primidone, Phenobarbital
–Type III antiepileptics - Ca++ channel inhibitors
•Ethosuximide, trimethadione
–Type IV - GABA promoters
•Vigabatrin, tiagabine, gabapentine
112

Phenytoin
•is one of the Na
+
channel inhibitor antiepileptic drugs
•Limited water solubility, slow, incomplete and variable
absorption
•Equal efficacy as phenobarbital but with lesser CNS
depressant effect
•It is highly plasma protein bound

Phenytoin cont…
•Adverse effects
–Acute toxicity - Results of over dosage
•Nystagmus, ataxia, vertigo, diplopia
–Chronic toxicity - Related to long term use
•Behavioral changes
•Gingival Hyperplasia (overgrowth of the gums)
•Enlargement of lips & nose
•Coarsening of facial features
•Hirsutism (excessive hairiness)

Carbamazepine
•Is highly efficacious & well tolerated, Na+ channel blocker
–Has fewer long term side effects than other anti-epileptics
•Metabolized in the liver by the CYP450 enzymes
–Enzyme inducer & can induce its own metabolizing enzyme as well as
enzymes of other drugs
•SEs:
–Drowsiness, headache, dizziness & incordination
–Allergic reactions, rare but sever aplastic anemia
–Most SEs occur at first therapy & tolerance develops
–Toxicity is low as compared to phenytoin

Ethosuximide
•Drug of choice for Absence seizure
–Not effective in other seizure types
•Blocks Ca
++
currents (T-currents) in the thalamus
•SEs
–GI complaints - Most common
–CNS effects - Drowsiness & lethargy
–Potentially fatal bone marrow toxicity and skin reactions
(both rare)

GABA transmission enhancers
1. Phenobarbital
–Is the only barbiturate with selective anticonvulsant effect
–Bind at allosteric site on GABA receptor & ↑ duration of
opening of Cl channel
–Inducer of microsomal enzymes → Drug interactions
–Toxic effects
•Sedation (tolerance develops), nystagmus, ataxia at higher
dose, osteomalacia, folate and vitamin K deficiency

GABA transmission enhancers cont…
2. Benzodiazepines
–Clonazepam, lorazepam & clorazepate
–Bind to another site on GABA receptor & increase frequency
of opening of the Cl- channel
–Are well absorbed from the GIT
–Metabolized by CYP450 enzymes to active metabolites
–Toxicities
•Lethargy, drowsiness, CNS sedation

GABA transmission enhancers cont…
3. Gabapentin - Developed as GABA analogue
–↑ release of GABA from gabanergic neurons by unknown
mechanism
4. Vigabatrin
–Irreversible inhibitor of GABA transaminase enzyme which
metabolizes GABA
5. Tiagabine
–↓ GABA uptake by neuronal and extraneuronal tissues so as
to increase GABA at the synapse

GABA transmission enhancers cont…
6. Valporic Acid
–Effective in the treatment of multiple seizure types
–Works by multiple mechanisms
•Blocks both Na+ & Ca++ channels and ↑ GABA activity
–Drug interactions: Inhibits metabolism of phenobarbital,
Carbamazepine & phenytoin
–Side effects
•Fatal hepatic failure (most serious SE), reversible hair
loss, ↑ in body weight, transient GI disturbances

Clinical Uses of Antiepileptic Drugs
•Tonic-clonic (grand mal) seizures:
–Carbamazepine preferred because of low incidence of
side-effects, phenytoin, valproate, Phenobarbital
– Use of single drug is preferred when possible, because of
risk of pharmacokinetic interactions
•Partial (focal) seizures:
–carbamazepine, valproate; clonazepam or phenytoin
are alternatives
121

Antidepressants
Depression
•Life-time prevalence is about 15 % although in women it is as high as 25%
•Typical symptoms
Depressed mood (feels sad or empty, tearful)
Loss of interest or pleasure
Decreased energy or increased fatigability
Loss of confidence or self-esteem
Unreasonable feelings of guilt
Recurrent thoughts of death or suicide
Agitation or retardation
Sleep and appetite disturbance

122

Depression
•Monoamine Hypothesis:
Depression is due to a deficiency of monoamine NTs, notably
nor-epinephrine (NE) and serotonin (5-hydroxytryptamine
[5HT])
Certain drugs that depleted these NTs could induce depression,
the tricyclic antidepressants and the MAO inhibitors with
pharmacological actions that boosted these neurotransmitters
are antidepressants
123

Tricyclic Antidepressants
•block norepinephrine and serotonin reuptake into the neuron
•TCAs also block serotonergic, α-adrenergic, histaminic, and
muscarinic receptors
Therapeutic uses:
•Treating moderate to severe depression
•Bed-wetting in children (imipramine)
•To treat migraine headache and chronic pain syndromes (neuropathic
pain) (amitriptyline)
•Insominia

124

Tricyclic Antidepressants
Examples Initial dose Max dose
Amitriptyline 30–75 mg 300mg
Clomipramine 10 mg daily 250mg
Doxepin 75 mg daily 300mg
Imipramine 75 mg daily 300mg
Nortriptyline 75 mg daily 150mg
Trimipramine 50mg daily 300mg
125

Tricyclic Antidepressants
•Adverse effects:
Antimuscarnic: blurred vision, xerostomia (dry mouth), urinary
retention, sinus tachycardia, constipation, and aggravation of
narrow-angle glaucoma
Block α-adrenergic receptors: orthostatic hypotension,
dizziness, and reflex tachycardia
Block histamine H
1 receptors: sedation, weight gain
Erectile dysfunction in men and anorgasmia in women
126

Monoamine Oxidase Inhibitors
•Monoamine oxidase (MAO) is a mitochondrial enzyme which
functions as a “safety valve” to oxidatively deaminate and inactivate
any excess neurotransmitter molecules (norepinephrine, dopamine,
and serotonin).
Therapeutic uses
•Depressed patients who are unresponsive or allergic to TCAs
•MAOIs are considered to be last-line agents

127

Monoamine Oxidase Inhibitors
Examples Initial dose Max dose
Phenelzine 15 mg 3 times daily 30mg TID
Isocarboxazid 30 mg daily 60mg daily
Tranylcypromine 10 mg twice daily 30mg
Moclobemide 300 mg daily 600mg
128

Monoamine Oxidase Inhibitors
Adverse effects
•Hypertensive crisis:
Tyramine, which is contained in certain foods, such as aged
cheeses and meats, chicken liver, preserved fish , and red wines,
is normally inactivated by MAO in the gut.
Individuals receiving a MAOI are unable to degrade tyramine
obtained from the diet. Tyramine causes the release of large
amounts of stored catecholamines from nerve terminals
Patients must, therefore, be educated to avoid tyramine-
containing foods.
129

Selective Serotonin Reuptake Inhibitors (SSRI)
•Specifically inhibit serotonin reuptake
•Have little blocking activity at muscarinic, α-adrenergic, and
histaminic H1 receptors
Common side effects associated with TCAs, such as
orthostatic hypotension, sedation, dry mouth, and blurred
vision, are not commonly seen with the SSRIs
•The drugs of choice in treating depression

130

SSRIs
Examples Initial dose Max dose
Citalopram 20 mg daily 40 mg daily
Escitalopram 10 mg daily 20 mg daily
Fluoxetine 20 mg daily 60 mg daily
Fluvoxamine 50 mg daily 300 mg daily
Paroxetine 20 mg daily 50 mg daily
Sertraline 50 mg daily 200 mg daily
131

SSRIs
•Therapeutic uses:
The primary indication for SSRIs is depression,
Other indications:
•Obsessive-compulsive disorder
•Panic disorder
•Generalized anxiety disorder
•Posttraumatic stress disorder
•Social anxiety disorder
•Premenstrual dysphoric disorder
132

SSRIs
•Adverse effects
SSRIs are considered to have fewer and less severe adverse
effects
Headache, sweating, anxiety and agitation, gastrointestinal (GI)
effects (nausea, vomiting, diarrhea), weakness and fatigue, sexual
dysfunction, changes in weight, sleep disturbances
133

Anesthetic Drugs
134

General Anesthesia
•Anesthesia usually involves loss of memory and awareness,
along with insensitivity to painful stimuli, during a surgical
procedure.
•GA depress the CNS to a sufficient degree to permit the
performance of surgery and other noxious or unpleasant
procedures.
•GA are usually administered by intravenous injection or by
inhalation.

135

Mechanism of Action
•Both the inhaled and the intravenous anesthetics can
depress spontaneous activity of neurons in many regions
of the brain.
•Primary molecular target of general anesthetics is the
GABA
A receptor-chloride channel, a major mediator
of inhibitory synaptic transmission
•Inhaled anesthetics, barbiturates, benzodiazepines, and
propofol facilitate GABA-mediated inhibition at GABA
A
receptor sites.
136

Stages of Anesthesia
Anesthetic drug effects can be divided in four stages of
increasing depth of CNS depression:
•Stage I (Stage of analgesia):
The subject is conscious but drowsy
Responses to painful stimuli are reduced
•Stage II (Stage of excitement):
Loses consciousness and no responds to non-painful stimuli
but responds to painful stimuli
The cough reflex and vomiting present
Can move, talk, hold his breath, choke or vomit
137

Stages of Anesthesia …
•Stage III (Stage of surgical anesthesia):
–Spontaneous movement ceases and respiration becomes
regular.
–Reflexes disappear, and muscles relax fully.
–Respiration becomes shallower, with the intercostal
muscles failing before the diaphragm.
•Stage IV (Stage of medullary paralysis):
–Respiration and vasomotor control cease, and death occurs
within a few minutes.
138

An ideal anesthetic
Have anxiolytic, sedative & analgesic activity
Does not bring about emesis
Counter act vagal activity
Cause muscle relaxation
Possess rapid induction & recovery
chemically stable, non-flammable, non-toxic & easy to
administer
Be inexpensive.
•No currently available anesthetic agent possesses all these
properties at tolerable doses

Anesthetics…
•Hence the need for pre-anesthetic medication arises to
produce a balanced anesthesia
Preanesthetic medication: is the use of drugs prior to
anesthesia to make it more safe and pleasant.
•To relieve anxiety – benzodiazepines.
•To prevent allergic reactions – antihistaminics.
•To prevent nausea and vomiting – antiemetics.
•To provide analgesia – opioids.
•To prevent bradycardia and secretion – atropine.

Balanced anesthesia
1.IV anesthetics
To induce anesthesia
To provide supplemental anesthesia
To permit anesthesia for short operative procedures
2.The inhalational anesthetics
Long term maintenance of the anesthetic state
3.Muscle relaxants
To facilitate tracheal intubation and optimize surgery
4.Opioid analgesics and cardiovascular drugs
β blockers, α
2 agonists, CCBs are used to control autonomic
responses to noxious (painful) surgical stimuli.
141

inhalational anesthetics: classification
A. Volatile liquids:
–Halogenated volatile anesthetics:
e.g. Halothane, enflurane, isoflurane, Desflurane,
Sevoflurane, methoxyflurane, trichlorethyline, ethyl chloride
–Ethers: Diethyl ether and divinylether (not used
nowadays due to their disadvantages) .
B. Anaesthetic gases:
– Nitrous oxide, cyclopropane and ethylene

P’kinetics of inhalational Anesthetics
•Anesthesia is produced when specific concentration is reached
at the site of action which depends on PK properties of the agent
•The depth of anesthesia depends on the potency of the
agent & it's partial pressure in the brain.
•Induction & recovery depend on the rate of change of partial
pressure in the brain.
•MAC (minimum alveolar concentration): is an index of potency
–MAC is an anesthetic dose expressed in percentage of the total gases
in inspired air which has an effect in 50% of the population.
–An anesthetic with low MAC is said to be potent

Factors affecting the partial pressure of an anesthetic
attained in brain
1.Partial pressure of anesthetic: inc. in Pa.P the more
ansethetic transferred to the blood
2.Pulmonary ventilation: Hyper ventilation will bring more
anesthetic per minute & respiratory depression will have the
opposite effect.
3.Solubility of the anesthetic in the blood
–Determines induction and recovery
–GA must first dissolve before its partial pressure is raised
–Drugs with low blood solubility (e.g. N
2o, desflurane) induce
quickly.
4.Solubility of anesthetic in tissue
–Determines its concentration in tissues
5.Cerebral blood flow
–increase cerebral blood flow increase induction

MOA of inhalational Anesthetics
•interactions of the inhaled anesthetics with proteins
comprising ion channels:
–increase the sensitivity of the GABA
A receptors to GABA
•causes a prolongation of the inhibitory Cl
-
ion current
after a pulse of GABA release.
•Postsynaptic neuronal excitability is thus diminished
•Other receptors are also affected
–Glycine receptor activation
–Blockage of nicotinic receptors

I. Volatile liquids
A.Halothane
•It is a clear colorless, volat‏‏ile liquid with chloroform like odour, non
inflammable and non explosive  Anesthetic of choice.
Pharmacological actions:
•CNS
–General anesthesia with rapid induction and recovery.
– cerebral blood flow.
– CSF pressure.
–Relaxation of skeletal muscles.
–Mild depression of respiratory centre.

Halothane….
C.V.S
–Bradycardia (due to vagal stimulation and direct depression of
SA node).
–Inhibition of cardiac contractility (due to  of IC Calcium).
–Hypotension (due to vasodilatation, cardiac depression,
depression of VMC and ganglionic blocking action).
GIT: Inhibition of tone and motility.
Uterus: Inhibition of uterine contractions.
Respiratory System: Bronchodilation and respiratory
depression.
Skeletal Muscles: Relaxation (but inadequate for abdominal
operations).

Halothane….
Therapeutic uses:
–Halothane is a
potent anesthetic, it is relatively weak analgesic  thus,
usually coadminstered with N2O, opioids or local anesthetics.
–Used in
obstetrics to induce uterine relaxation
–In children for inhalation induction (unlike adults, not hepatotoxic)
PK
–Metabolized to tissue-toxic hydrocarbons and bromide ion (responsible
for toxic rxn)
•fever, followed by anorexia, nausea, and vomiting, and patients
may exhibit signs of hepatitis. (to avoid this, halothane anesthesia
should not be repeated at less than 2-3wk)

Halothane….
Adverse effects:
•Hepatotoxicity
•CVS
–Bradycardia
–cardiac arrhythmias
–concentration-dependent hypotension (better to give direct
acting vasoconistrictor, such as phenylepherine)

Halothane‏…
Advantages of halothane:
–pleasant smell, there fore is accepted by many patients
–Very potent anesthetic (MAC= 0.75%)
–Non-irritant
–Bloodless field for plastic surgery because of the fall in
blood pressure.
–Solubility in blood is intermediate  reasonable induction &
recovery.
–No post operative nausea & vomiting
–No bronchospasm, no coughing, hence suitable for tracheal
intubation.

Halothane‏…
Disadvantages of halothane:
–Little analgesic activity
–Little muscle relaxation
–Fall in blood pressure because of myocardial depression
–Expensive

151

B. Enflurane
• A halogenated compound
•This gas is less potent than halothane, but it produces rapid induction
and recovery.
•2% is metabolized to F
-
Excreted by Kidney C/I in kidney
failure
•It differs from halothane in that
–fewer arrhythmias
–less sensitization of the heart to catecholamines
–greater Potentiation of muscle relaxants due to a more potent
‘curare-like’‏effect •Disadvantages:
–CNS excitation (not used in patients with seizure disorder)

C. Isoflurane
•A recently introduced isomer of enflurane, more potent, more volatile & less
soluble in blood
•Advantage
–Undergoes little metabolism little fluoride ion produced.
–does not induce cardiac arrhythmias and does not sensitize the heart to
the action of catecholamines.  beneficial in patients with
ischemic heart disease
–Muscle relaxation
–No myocardial depression, No hepatotoxicity
•Disadv:
–Un-pleasant odour, Resparatory depression
–Hypotension because of the decreased peripheral vascular resistance.
•Therapeutic status: widely used

D. Nitrous oxide (gas Anesthetic)
•a potent analgesic but a weak general anesthetic - combined
with other, more potent agents to attain pain-free anesthesia.
•poorly soluble in blood and other tissues
–move very rapidly in and out of the body.
•does not depress respiration, nor does it produce muscle
relaxation.
causes excitement at high concentration therefore the name
laughing gas is given.
•rapid induction & recovery, non-irritant, not flammable, very
potent analgesic activity, little effect on respiration, heart &
blood pressure

2. IV Anesthetics
•Thiopental, Methohexital, Etomidate, Ketamine, and
Propofol
•are used for the rapid induction of anesthesia, then maintained
with an appropriate inhalation agent.
•They rapidly induce anesthesia and must therefore be injected
slowly.
•Recovery from intravenous anesthetics is due to
redistribution from sites in the CNS.

A. Ultra–short Acting Barbiturates
–Thiopental , Thiamylal & Methohexal
Thiopental
•a potent anesthetic and a weak analgesic  require a supplement
of analgesic Admn.
•Has a high lipid solubility, they quickly enter the CNS & depress
function, often in less than 1 minutes
•Very rapid
redistribution results recovery from anesthesia
•Metabolized relatively slowly by liver enzyme.
Adverse Drug Effect
–minor effects on CVS, but in patients with hypovolumia or shock
severe hypotension.
–apnea, coughing, chest wall spasm, laryngospasm, and
bronchospasm. (concern for Asthma)

B. Benzodiazepines (Midazolam, Diazepam & lorazepam)
•As preanesthetic medication & adjuvant in local anesthesia.
•Diazepam and Lorazepam are not water-soluble, and their IV use
necessitates non-aqueous vehicles, which cause pain and local
irritation.
•Midazolam is water-soluble and is the BZP of choice for
parenterally administration (at physiologic pH midazolam becomes
lipid-soluble and can cross the BBB to produce its central effects)
•Slow onset of action compared with other IV anesthetics
•Midazolam has more rapid onset, short half-life than other BZPs
•FLUMAZENIL – can be used to accelerate recovery when excessive
dose of iv bzps are administered.

C. Opioid Analgesics
–Fentanyl, sufentanil, remifentanil, alfentanil
•IV, Epidurally, or Intrathecally.
•Analgesic property used together with anesthetics
•High doses OAs + large doses of BZPs for major
cardiovascular surgical procedures
•Fentanyl + droperidol to produce analgesia and amnesia and
combined with N2O provide a state referred to as
neuroleptanesthesia
Adverse drug event: Hypotension, Respiratory Depression, and Muscle
Rigidity, post-anesthetic nausea and vomiting
•Opioid effects can be antagonized by Naloxone

D. Ketamine
•a short-acting, nonbarbiturate anesthetic
•induces a Dissociative Anesthesia
–the patient is unconscious but appears to be awake and
does not feel pain.
–provides sedation, amnesia, and immobility with or without
loss of consciousness (hypnosis)
MOA
•blockade of the membrane effects of the excitatory
neurotransmitter glutamic acid at the NMDA receptor
subtype

Ketamine …..
•highly lipophilic drug and is rapidly distributed into well-
perfused organs (the brain, liver, and kidney).
•the only intravenous anesthetic that possesses anesthetic and
analgesic properties, as well as the ability to produce dose-
related cardiovascular stimulation.
•Adverse Effect
–postoperative disorientation
–sensory and perceptual illusions
–vivid dreams

E. Propofol
•intravenous sedative/hypnotic used in the induction or
maintenance of anesthesia (onset with in 40 sec).
•Narcotics are required for analgesia
•Replaced thiopental
•Doesn’t‏cause‏postanesthetic nausea and vomiting
•Useful for spinal surgeries
•Accompanied by muscle twitching, spontaneous movement, or
hiccups.
•Propofol decreases blood pressure without depressing the
myocardium.

E. Etomidate
•A hypnotic agent but lacks analgesic activity
•Poor water solubility, so is formulated in a propylene glycol
solution.
•Rapid but short-acting
•only used for patients with coronary artery disease or
cardiovascular dysfunction, such as shock.
•ADE
–decrease in plasma cortisol and aldosterone levels

Local Anesthetics
•Local anesthesia involves loss of sensation and motor activity
in localized areas of the body.
•Prevent responding to pain impulses and other sensory
stimuli.

163

Classification of Local Anesthetics
1. Topical or Surface anesthesia
Applied to skin or mucous membrane
Used to treat pain, itching stimuli on conjunctiva, larynx,
throat, hemorrhoids, damaged skin
Benzocaine, cocaine, pramoxine
2. Infiltration anesthesia
Injected directly into or very close to the area to be
anesthetized.
Used during tooth extraction, surgical incision
Etidocaine, lidocaine, prilocaine & tetracaine

Classification of local anaesthetics
3. Nerve block anesthesia
–Injected as close as possible to the nerve trunk supplying the
specific area to be anesthetized.
–Enable minor operations on the limb
–Lidocaine, mepivacaine, bupivacaine
4. Spinal anesthesia
–Injecting the anesthesia in to CSF, usually in the lumbar spine.
–The anesthesia blocks sensory impulses at the root of peripheral
nerves as they enter the spinal cord.
–Useful for surgery of lower abdomen & legs.
–Procaine, tetracaine

Role of vasoconstrictors
•Vasoconstrictors: are mostly incorporated into LAs their
function is
–To decrease absorption  decrease metabolism & decrease
toxicity
–Enhance neuronal uptake of the LA

Pharmacology for pharmacy students @2.pd

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