Pharmacology of agents used for

treatment of sexual and

reproductive tract infections

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 STI versus STD
STI Infections acquired through sexual
intercourse (may be symptomatic or
asymptomatic)
STD Symptomatic disease acquired through
sexual intercourse
STI is most commonly used because it applies
to both symptomatic and asymptomatic
infections

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 STI
Infections that are most commonly passed through
sexual contact
Gonnorhea
Chlamydia
Syphilis
chancroid

Genital herpes
Hepatitis B
HIV
HPV (human papillomavirus)

Candidiasis (yeast infection)

Trichomoniasis

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 Bacterial vs. Viral STIs
Bacterial STIs include Viral STIs include HPV, HIV,
Chlamydia, gonorrhea & Herpes, & Hepatitis B
syphilis There is NO cure
Can be treated and cured Medication available to
with antibiotics treat symptoms only
Untreated infection can Can pass onto others for the
cause PID, infertility, & rest of your life
epididymitis

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 Drug treatments
Genital herpes
Hepatitis B
HIV
HPV(human papillomavirus)

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 Genital herpes
Genital herpes is caused by infection with herpes
simplex (HSV) type 1 and 2.
While both HSV-1 and HSV-2 can be sexually
transmitted, most genital herpes infections are
caused by HSV-2 ( in Ethiopia only HSV-2 is
identified)
First line
Acyclovir
Alternatives
Valacyclovir or Famiciclovir

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Acyclovir (Zovirax)
What?
It is a guanine analogue
MOA?
Acyclovir is monophosphorylated by a herpes
enzyme called thymidine kinase.
Later it is di- and triphosphorylated by the host
cell.
The active triphosphate form of acyclovir is then
incorporated into viral DNA, which causes
premature DNA-chain termination

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HPV
Warts are caused by infection with Human
Papilloma Virus (HPV).
epidemiologically linked to the development
of cervical cancer in women
Genital warts can be treated using strong
acids and chemicals, topical cream, electric
currents or laser therapy
Surgical: For extensive warts
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 Hepatitis B
There is no cure for hepatitis B, but a vaccine to
prevent the infection is available
If an individual is exposed, an injection of
antibodies may be given (up to 7 days after a
needlestick injury and up to 14 days after sexual
contact), followed by vaccine to help prevent
infection
Those who develop chronic hepatitis B require
monitoring of their liver function and may benefit
from treatment with interferon or an anti-viral
medication
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 Trichomoniasis
trich is a very common STD that is caused by infection
with a protozoan parasite called Trichomonas vaginalis.
Common curable STD
The parasite is passed during sex
About 70% of infected people do not have any signs or
symptoms
Affect:
lower genital tract (vulva, vagina, or urethra),
in men, the inside of the penis (urethra)

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 Trichomoniasis
treatment
First line
Metronidazole 2 g PO in a single dose
Alternative
Tinidazole 2 g PO in a single dose

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 Metronidazole
A nitroimidazole
Note: also used in the treatment of infections
caused by:
Giardia lamblia, E. histolytica , anaerobic cocci,
and anaerobic gram-negative bacilli (for example,
Bacteroides species).
it is the drug of choice for the treatment of
pseudomembranous colitis caused by the
anaerobic, gram-positive bacillus Clostridium
difficile
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 Mechanism of action:
Some protozoal parasites possess ferrodoxin-like
electron-transport proteins that participate in
metabolic electron removal reactions.
The nitro group of metronidazole is able to serve
as an electron acceptor, forming reduced cytotoxic
compounds that bind to proteins and DNA,
resulting in cell death

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parasite

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 disulfiram like -effect
When metronidazole is given with alcohol
abdominal distress, nausea, vomiting, flushing,
or headache, tachycardia, hyperventilation

alcohol aldehyde
dehydrogenase dehydrogenase

Ethanol Acetaldehyde Acetate

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 CANDIDIASIS
Candidiasis is an infection caused by yeast like fungus Candida albicans

Common drugs
Nystatinantifungal antibiotics
Clotrimazole, Miconazolsynthetic antifungals

Route of administration: topical

Dosage form:
Cream
pessary
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 Nystatin
Nystatin is a polyene antibiotic, and its structure,
chemistry, mechanism of action, and resistance
resemble those of amphotericin B.
Its use is restricted to topical treatment of Candida
infections because of its systemic toxicity.
The drug is negligibly absorbed from the
gastrointestinal tract, and it is never used parenterally.
Adverse effects are rare because of its lack of
absorption, but Nausea and vomiting can occur.

Nystatin

Amphotericin B

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 M.OA.= Binds to
Ergosterol (specific to
fungi) and forms pores
or channels within the
membrane.
This allows electrolytes
to leak from the cell,
which results in cell
death.

Selective toxicity???

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 SYNTHETIC ANTIFUNGAL AGENTS
Azoles
Imidazoles or Triazoles
Imidazoles ketoconazole, miconazole, clotrimazole
Triazoles itraconazole, fluconazole, voriconazole and
posaconazole.

Most useful against Histoplasma but can be used against Candida, Cryptoccus,
Blastomyces and Dermatophytes
Relatively nontoxic, minor gastrointestinal upset
All Azole drugs affect the mammalian cytochrome P450 (prone to drug
interactions)

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Topical Azoles (Clotrimazole, Miconazole)

Miconazole and clotrimazole are topically

active drugs that are only rarely administered
parenterally because of their severe toxicity.
Their mechanism of action and antifungal
spectrum are the same as those of
ketoconazole.
Topical use is associated with contact
dermatitis, vulvar irritation, and edema.

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 Topical Azoles (Clotrimazole, Miconazole)
Miconazole is a potent inhibitor of warfarin metabolism and
has produced bleeding in warfarin-treated patients even when
miconazole is applied topically.

No significant difference in clinical outcomes is associated with

any azole or nystatin in the treatment of vulvar candidiasis.

Miconazole
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 Drug treatments of bacterial STIs
Syphilis
Benzathine penicillin
Alternative
Doxycycline or Tetracycline or erythromycin

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Chlamydia
Infection with Chlamydia trachomatis is a
major cause of urethritis in males and
cervicitis in females
First line
Doxycycline
Alternatives
Tetracycline or azithromycin or erythromycin
or levofloxacin

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Gonorrhea
Gonorrhea is a common sexually transmitted infection
caused by the gram negative diplococci, Neisseria
gonorrhoeae
Effective treatment of gonorrhea routinely includes a
single dose of anti-gonococcal agent plus a course of
therapy to eradicate possible co-infection with C.
Trachomatis
First line
Ciprofloxacin, 500 mg P.O. single dose PLUS Doxycycline,
100mg PO BID for 7 days
Alternatives
Ceftriaxone, 250mg IM single dose or
Norfloxacin, 800 mg PO single dose
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Chancroid
Chancroid is an ulcerative disease of the genitalia
caused by infection with Haemophilus ducreyi
First line
Azithromycin, 1.0 gm PO, single dose
Alternative
Ceftriaxone, 250 mg IM, single dose or
Ciprofloxacin, 500 mg P.O.BID for 3 days or
Erythromycin base, 500 mg P.O. QID for 7 days or
Amoxicillin-Clavulanic acid, 625 mg P.O.TID for 7
days

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 Drugs for bacterial STIs
Gonnorhea
Chlamydia
Syphilis
chancroid

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 Classification of antibacterials
I. based on their proposed mechanism of action
Cell wall synthesis inhibitors
Protein synthesis inhibitors
Plasma membrane-injuring agents
Nucleic acid inhibitors
Metabolic/enzyme inhibitors

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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 -lactam ring fused
with a thiazolidine nucleus

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 Penicillins

Antimicrobial activity of penicillin resides in the -lactam ring

Splitting of the -lactam ring by either acid hydrolysis or -

lactamases results in the formation of penicilloic acid, a
product without antibiotic activity

Addition of various side chains (R) to the basic penicillin

molecule creates classes of compounds with the same
mechanism of action
But with different chemical and biological properties

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 Modifications that are performed on the R-side chain of
aminopenicillanic acid determine
Affinity for PBPs

Resistance to penicillinases

Ability to penetrate the gram negative cell envelope

Resistance to stomach acid and

Pharmacokinetic properties of the penicillins

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 Classification
Based on their antimicrobial spectrum, penicillins can be
classified into 4 classes:
1. Natural penicillins: Penicillin G, Penicillin V

2. Anti-staphylococcal penicillins (penicillinase resistant

penicillins): Nafcillin, oxacillin, cloxacillin, dicloxacillin

3. Aminopenicillins: ampicillin, amoxicillin

4. 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 gastrointestinal tract 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
Or
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 .
Therapeutic Uses
Pen G is a drug of choice for infections caused by:
Streptococci, Meningococci, gonococci, actinomycosis
Non-lactamase producing staphylococci
Treponema pallidum and non- -lactamase producing
gram-negative anaerobic organisms

Penicillin V
Penicillin V is used to treat mainly streptococcal
infections when oral therapy is appropriate and desirable

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 -Lactamase Inhibitor Combinations
Several formulations combine a -lactam antibiotic
with a -lactamase inhibitor

Clavulanic acid
o It is combined with amoxicillin for oral administration
o AUGMENTIN
o and with ticarcillin for parenteral administrition
o TIMENTIN
Sulbactam
combined with ampicillin for IV or IM use
UNASYN
Tazobactam
It has been combined with piperacillin as a parenteral preparation
ZOSYN
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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 -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 -
lactam antibiotic should avoid all other -lactam antibiotics
except aztreonam

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 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
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 Tetracyclines
Are broad spectrum antibiotics which are synthesized
by a number of streptomyces species
Includes:
Tetracycline
Oxytetracycline
Tigecycline
Chlortetracycline
Minocycline
Demeclocycline
Doxycycline
Their principal difference is pharmacokinetics
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 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)
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 Pharmacokinetics of TTCs
Absorption
Oral absorption of most tetracyclines is incomplete
The percentage of an oral dose that is absorbed with
an empty stomach is:-
Low for chlortetracycline (30%)
Intermediate for oxytetracycline, demeclocycline, and
tetracycline (60% to 80%)
High for doxycycline (95%) and minocycline (100%)

Absorption is greater in the fasting state

Absorption of tetracyclines is impaired by the
concurrent ingestion of dairy products; aluminum
hydroxide gels; calcium, magnesium, and iron or
zinc salts; and bismuth subsalicylate 49
 Pharmacokinetics of TTCs..

Distribution
Tetracyclines distribute widely throughout the body and
into tissues and secretions, including urine, maternal
circulation, amniotic fluid, CSF, breast milk, bone marrow,
bone etc
Excretion
With the exception of doxycycline & minocycline the
primary route of elimination for most tetracyclines is the
kidney
Doxycycline & minocycline is excreted in the feaces

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 Adverse effects of TTCs
They have strong affinity for calcium
Discoloration of permanent teeth in fetuses and children
May retard fetal bone development if taken during
pregnancy
So TTCs are not given for children < 8 years old & pregnant
mother after 4 months
Hepatotoxicity occurs infrequently
Most are nephrotoxic, so not give with other nephrotoxic
agents
Photosensitivity
Abnormal sunburn reactions
Associated particularly with
Demeclocycline
Doxycycline 51
 Macrolides
group of antibiotics which have a large lactone ring
to which one or more deoxy sugars are attached.
Includes:
erythromycin ..parent drug
azithromycin & clarithromycin semisynthetic
derivatives
These structural modifications improve acid stability
and tissue penetration and broaden the spectrum of
activity

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 Pharmacokinetics
Erythromycin base
is incompletely but adequately absorbed from the upper
small intestine
administered as enteric-coated tablets or as capsules to
prevent inactivation by gastric acid
Food may delay absorption by increases gastric acidity

Azithromycin
administered orally & absorbed rapidly
should not be given with food
is available for IV infusion

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 Therapeutic (clinical) Uses
1. Prevention & treatment of staph., strept & pneumococcal
infections in patients with hypersensitivity to penicillin
2. Otitis media & sinusitis as they are caused by bacteria
sensitive to Macrolides (strept, pneumococcal & H.
influenza)
3. Syphilis & gonorrhea (2nd choice drug)
4. Diphtheritic pharyngeal carrier eradication (1st choice
drug)
5. Chlamydial infection in pregnant (Not teratogenic) &
infants
6. Mycoplasma pneumonia in infants

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 Therapeutic (clinical) Uses

7- Chlamydial & gonococcal urethritis, cervicitis, pelvic

infection (treated by Azithromycin)

8- Legionellosis (treated by Azithromycin)

9- Toxoplasmosis (treated by Clarithromycin)

10- Helicobacter Pylori in peptic ulcer (treated by

Clarithromycin)

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 Adverse effects
1. Epigastric distress
Common & can lead to poor patient compliance for
erythromycin
Clarithromycin & azithromycin are better tolerated by the
patient, but GIT problems are their most common side
effects .
2-Cholestatic jaundice:
especially with the estolate form of erythromycin
3-Ototoxicity:
Transient deafness associated with high dosages of
erythromycin
4- Erythromycin has been reported to cause cardiac
arrhythmias
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 Quinolones
Naldixic acid is the first quinolone.
Its use is limited to urinary and GI infections
It is excreted too rapidly.
Fluorination of the quinolone structure floroquinolones
with high potency
better tissue penetration and
good tolerability.

They are bactericidal

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 Quinolones
Mechanism of action
block bacterial DNA synthesis by inhibiting bacterial
Topoisomerase II (DNA gyrase) and topoisomerase IV
interferes with separation of replicated chromosomal DNA in
to the respective daughter cells during cell division.

Resistance
The structural modification of the DNA gyrase or
Topoisomerase IV &
efflux pumps
There are no quinolone inactivating enzymes by the
bacteria
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 Quinolones
Antibacterial activity
Floroquinolones have excellent activity against Gm
aerobic bacteria.
They have limited activity against Gm+ organisms.
Norfloxacine is the least active of floroquinolones
against both Gm+ and Gm- organisms.
Ciprofloxacin possesses excellent Gm- activity and
moderate to good activity against Gm+ bacteria.

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 Quinolones
Drug interactions:
absorption: Al3+, Mg2+, and Ca2+ antacids can
decrease the absorption of floroquinolones
CYP450 inhibition potential drug interactions for
ciprofloxacin
E.g. it can increase warfarin serum concentration
Contraindications:
patients under 18 years of age
nursing mothers and pregnant women.
Floroquinolones may damage growing cartilage and cause
an arthropathy.

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