Transcript Antitubercular Drugs

TB
 Tuberculosis is a chronic
granulomatous disease and a major
health problem in developing
countries.
 About 1/3rd of the world’s population
is infected with Mycobact.
tuberculosis.
 The increase in TB associated with
HIV infection
 Emergence of ‘multidrug resistant’
(MDR) TB which now accounts for
15% of previously treated, and 3% of
new TB cases worldwide, is
threatening the whole future of
current antitubercular chemotherapy.
Anti-TB drugs
First line drugs:
 1. Isoniazid
 2. Rifampicin
 3. Pyrazinamide
 4. Ethambutol
 5. Streptomycin
First line:
 These drugs have high antitubercular efficacy;
 are used routinely.
Second line drugs:
 Para-aminosalicylic acid (PAS)
 Kanamycin
 Amikacin
 Ethionamide
 Prothionamide
 Fluoroquinolones (Ofloxacin ,
Levofloxacin, Moxifloxacin,
Ciprofloxacin)
Second line:
 These drugs have either low antitubercular efficacy or
higher toxicity or both;
 are used as reserve drugs.
Alternative grouping of antitubercular drugs
 Group I (high efficiency):
Isoniazid, Rifampicin.
 Group II (average efficiency):
Streptomycin, Kanamycin, Viomycin, Cycloserine, Ethambutol,
Ethionamide, Protionamid, Pyrazinamide.
 Group III (low efficiency):
PAS, thioacetazone.
 The highest activity against Mycobac. tuberculosis are isoniazid
and rifampicin, so the strategy of modern chemotherapy for
patients with new diagnosed tuberculosis are based on
combinations of these drugs.
 The combination of isoniazid and rifampicin with other anti-TB
drugs 1st line (pyrazinamide, streptomycin and ethambutol) can
achieve cure most patients.
 2nd line drugs(reserve), are used only for the treatment of
multidrug resistant tuberculosis.
Anti-TB drugs














Isoniazid
One of the most effective anti-TB drugs (1st line).
Bactericidal effect on mycobacteria in the process of reproduction, bacteriostatic - in the resting
stage.
The most frequent ADR: neurotoxicity(paresthesias, numbness, mental disturbances,
convulsions), hepatotoxicity
Prophylactic use of pyridoxine
Rifampicin
st
One of the most active anti-TB drugs (1 line).
Bactericidal activity.
The most frequent HP: hepatotoxicity.
Can colour urine, sputum and saliva in red.
Rifabutin
nd
Anti-TB drugs (2 line). The structure and properties similar to rifampicin.
Differences:
- more active against atypical mycobacteri; bioavailability does not depend on food intake;
- can cause uveitis;
- interacts with fewer drugs;
- not applied to children up to 14 years
Pyrazinamide
anti-TB drugs (1st line), with an average efficiency.
Weak bactericidal effect.
Produce "sterilizing" effect. Low toxicity.
The most frequent ADR: gastrointestinal ADRs
Anti-TB drugs









Ethambutol
Anti-TB drugs (1st line), with an average efficiency.
Bacteriostatic action. Low toxicity.
Act only on fast multiplying bacilli.
The most frequent ADR: gastro-intestinal and visual
disturbances (visual control)
PAS
Anti-TB drugs (2nd line) with low efficiency.
Bacteriostatic action. Average toxicity.
Poorly tolerated due to frequent ADR – GIT
Does not add the efficacy for more active drugs
Only delays development of resistance
Anti-TB drugs
Streptomycin
 Because of need for i.m. injections and lower margin
of safety (ototoxicity and nephrotoxicity)
Streptomycin is used only as an alternative to or in
addition to other 1st line anti- TB drugs.
 Use is restricted to a maximum of 2 months.
 It is thus also labelled as a ‘supplemental’ 1st line drug.
Syphilis
Syphilis
 A sexually transmitted infection caused by
Treponema pallidum.
 The primary stage classically presents with
a single chancre (a firm, painless, non-itchy
skin ulceration)
 In secondary syphilis a diffuse rash which
frequently involves the palms of the hands
and soles of the feet occurs. There may also
be sores in the mouth or vagina.
 In latent syphilis there are little to no
symptoms which can last for years.
 In tertiary syphilis there are gummas (soft
non-cancerous growths), neurological, or
heart symptoms.
 It may also be transmitted from mother to
baby during pregnancy or at birth, resulting
in congenital syphilis.
 Syphilis has been known as "the great
imitator" as it may cause symptoms similar
to many other diseases.
Treatment
 The first-choice treatment for syphilis
remains a single dose of intramuscular
benzathine penicillin G.
 Doxycycline and tetracycline are
alternative choices for those allergic to
penicillin; due to the risk of birth
defects these are not recommended for
pregnant women.
 Ceftriaxone, a third-generation
cephalosporin antibiotic, may be as
effective as penicillin-based treatment
if a person is allergic.
Anthelmintic Drugs
 Anthelmintics are drugs
that either kill (vermicide)
or expel (vermifuge)
infesting helminths.
 Helminthiasis is prevalent
globally (1/3rd of world’s
population carriers them),
but is more common in
developing countries with
poorer personal and
environmental hygiene.
Helminthiases
 Helminthiasis also known as worm infection, is any
macroparasitic disease of humans in which a part of the
body is infected with parasitic worms, known as helminths.
 Helminths are classified into:
 Tapeworms (Cestoda- Taenia solium,T. saginata,
Diphyllobothrium)
 Flukes (Trematoda- Clonorchis sinensis and Fasciola
hepatica)
 Roundworms-(Nematodes- ascarids (Ascaris), filarias,
hookworms, pinworms (Enterobius) and whipworms
(Trichuris trichiura))
 Helminthiasis is rarely fatal, but is a major cause of chronic
illness, malnutrition, and anemia as secondary effects.
Anthelmintics or antihelminthics
1) Broad-spectrum benzimidazoles are the first line
treatment of gastrointestinal parasites:
 Mebendazole -effective against roundworms
 Albendazole- effective against roundworms and
tapeworms.
2) Pyrantel, Levamisole, Ivermectin are effective against
adult and migrating larval stages of roundworms.
3) Praziquantel is the drug of choice for flatworms.
4) Artemisinins are proving to be candidates as drugs of
choice for trematodiasis/Flukes
Mebendazole
 It has produced nearly 100% cure rate/reduction in egg
count in roundworms.
 The immobilizing and lethal action on worms
Mechanism of action
 It binds to microtubular proteins of the parasite and
inhibits its polymerization → It blocks glucose and
other nutrients uptake in the parasite → the gradual
immobilization and eventual death
Adverse effects (well tolerated):
 Diarrhoea, nausea and abdominal pain
 Allergic reactions
Albendazole
It is effective first-line of treatment against:
 Flatworms
 Flukes/trematodes
 Tapeworm/cestodes
 Nematodes
Other uses
 As an antiprotozoal agent, it may be used against
giardiasis and microsporidiosis.
Praziquantel
 is the drug of choice for flatworms infections
Mechanism of action
 act by causing leakage of intracellular calcium from the
membranes →contracture and paralysis.
 Selectivity of action on tapeworms and flukes.
Adverse effects
 It tastes bitter: can produce nausea and abdominal pain.
 Headache, dizziness and sedation.
 Allergic reactions
Pyrantel
 It was introduced in 1969 for pinworm infestation in






children
Efficacy against Ascaris, Enterobius and Ancylostoma
is high and comparable to that of mebendazole.
Mechanism of action
Pyrantel causes activation of N-cholinergic receptors
in the worms → persistent depolarization → slowly
developing contracture and spastic paralysis.
Cholinergic receptors in mammalian skeletal muscle
have very low affinity for pyrantel.
Adverse effects
occasional g.i. symptoms, headache and dizziness
Levamisole
 Active against many nematodes, but use is restricted to
ascariasis and ancylostomiasis as a second line drug.
 Mechanism of action
 The ganglia in worms are stimulated causing tonic
paralysis and expulsion of live worms.
 Levamisole is an immunomodulator as well: restores
depressed T cell function.
 Adverse effects
 One or two doses used in helminthiasis are well
tolerated.
 Nausea, abdominal pain, fatigue, drowsiness.
Ivermectin
 Ivermectin is the drug of choice for single dose treatment
of onchocerciasis and strongyloidosis.
 Ivermectin is also highly effective in cutaneous larva igrans
and ascariasis
 Ivermectin is the only drug effective orally in scabies and
pediculosis
Mechanism of action
 It acts through a special type of glutamate gated Cl¯
channel found only in invertebrates. Such channels are not
involved in the motor control of flukes and tapeworms
which are unaffected by ivermectin →Nematodes develop
tonic paralysis
Side effects
 Pruritus, giddiness, nausea, abdominal pain, constipation,
lethargy and transient ECG changes
Antiprotozoal Drugs
 Protozoan infections are
parasitic diseases caused
by organisms formerly
classified in the
Kingdom Protozoa.
 Examples include
Entamoeba histolytica,
Plasmodium, Giardia
lamblia, Trypanosoma,
etc.
ANTIAMOEBIC DRUGS
CLASSIFICATION
1. Tissue amoebicides
(a) For both intestinal and
extraintestinal amoebiasis:
Nitroimidazoles: Metronidazole,
Tinidazole, Ornidazole
Alkaloids: Emetine, Dehydroemetine
(b) For extraintestinal amoebiasis only:
Chloroquine
2. Luminal amoebicides
(a) Amide : Diloxanide furoate,
Nitazoxanide
(b) 8-Hydroxyquinolines: Iodoquinol
(c) Antibiotics: Tetracyclines, Paromomycin
NITROIMIDAZOLES
 It has broad-spectrum cidal activity against anaerobic
protozoa (Giardia lamblia, Trichomonas vaginalis,
Entamoeba histolytica)+ Clostridium perfringens, Cl.
difficile, Helicobacter pylori, Campylobacter, peptococci,
spirochetes and anaerobic Streptococci are sensitive.
Uses:
 Amoebiasis (first line drug for all forms of amoebic infection)
 Giardiasis
 Trichomonas vaginitis (It is the drug of choice)
 Anaerobic bacterial infections (They occur mostly after colorectal or
pelvic surgery,appendicectomy, etc)
 Pseudomembranous enterocolitis (due to Cl.difficile)
 Helicobacter pylori gastritis/peptic ulcer
 Guinea worm infestation (the drug of choice)
NITROIMIDAZOLES
Adverse effects
 Side effects are frequent and unpleasant, but mostly
nonserious.
 Anorexia, nausea, metallic taste and abdominal
cramps, diarrhea
 Allergic reactions
 Prolonged administration may cause peripheral
neuropathy and seizures
Emetine, Dehydroemetine
 Alkaloids from Cephaelis ipecacuanha.
 Directly acting amoebicides—kills trophozoites but has no
effect on cysts.
 It is highly efficacious in amoebic liver abscess also.
 Emetine cannot be given orally because it will be vomited
out(due to CTZ stimulation and gastric irritation),.
 It is administered by s.c. or i.m. injection
ADR:
 High systemic toxicity (nausea, vomiting, abdominal
cramps, diarrhoea, weakness, stiffness of muscles, myositis,
hypotension, ECG changes and myocarditis).
Use
 now rarely used only in patients not tolerating
metronidazole.
Chloroquine
 Highly concentrated in liver.
 Therefore, it is used in hepatic amoebiasis only.
 It is employed only when metronidazole fails to clear
the infection or is not tolerated.
Diloxanide furoate





FURAMIDE
It is a highly effective luminal amoebicide
which directly kills trophozoites responsible
for production of cysts.
Poor tissue amoebicidal action.
However, a single course produces high
(80%) cure rate in mild intestinal amoebiasis
and in asymptomatic cyst passers.
ADR:
Flatulence, occasional nausea, itching and
rarely urticaria.
 It is a preferred drug for mild
intestinal/asymptomatic amoebiasis, and is
given after or along with any tissue
amoebicide to eradicate cysts.
 Combined use with
metronidazole/tinidazole is quite popular.
Some chronic cases require repeat courses
for eradication.
Nitazoxanide
 Nitazoxanide is the most effective
drug for Cryptosporidium parvum
infection (upto 88% cure), which
causes diarrhoea, especially in
children and AIDS patients.
 It is also indicated in giardiasis,
and in amoebic dysentery as
luminal amoebicide.
Side effects:
 Abdominal pain, vomiting and
headache
Iodoquinol
 Are active against Entamoeba, Giardia, Trichomonas
 In intestinal amoebiasis as alternative to diloxanide
furoate.
Side effects:
 Nausea, transient loose and green stools, pruritus,
 Iodism (furunculosis, inflammation of mucous
membranes) due to chronic iodine overload. Goiter may
develop. Individuals sensitive to iodine may experience
acute reaction with chills, fever, angioedema and
cutaneous haemorrhages.
 Prolonged/repeated use more than 14 days can cause
neuritis and optic damage (blindness).
ANTIBIOTICS








Tetracyclines
direct inhibitory action on Entamoeba
with a more efficacious luminal amoebicide
Paromomycin
It is an aminoglycoside antibiotic
is active against many protozoa like Emtamoeba, Giardia,
Cryptosporidium, Trichomonas, Leishmania
Orally administered paromomycin acts only in the gut
lumen. It is neither absorbed nor degraded in the ntestines,
and is eliminated unchanged in the faeces.
In India and Africa, parenteral (i.m.) paromomycin is being
used in resistant Kala-azar
Side effects:
nausea, vomiting, abdominal cramps, diarrhoea
DRUGS FOR GIARDIASIS
 Giardia lamblia is a flagellate protozoon which infects
children and adults by oro-faecal contamination and
mostly lives in the intestine.
 It causes acute watery short duration diarrhoea with
foul smellling stools, gas and abdominal cramps.
 Metronidazole (drug of choice)
 Nitazoxanide
 Paromomycin
DRUGS FOR TRICHOMONIASIS
 Trichomonas vaginalis is protozoon which causes
vulvovaginitis.
 It is a common sexually transmitted disease affecting ~
10% sexually active women.
Drugs used orally
 Metronidazole (drug of choice)
Additional intravaginal drugs
 Iodoquinol
 Povidone-iodine
DRUGS FOR LEISHMANIASIS
Visceral leishmaniasis (kala-azar)
Leishmania donovani
 Is fatal unless treated
Dermal leishmaniasis (oriental sore)
L. braziliensis and L. tropica
 Not a life-threatening
condition
 Amphotericin B (AMB)
 Miltefosine
 Local application of drugs:
 Sodium stibogluconate (or
 Sodium stibogluconate
Meglumine antimonate—in
French speaking countries)
 Paromomycin
 Paromomycin (15%)
ointment
Leishmaniasis is transmitted by the bite of
the female sandfly phlebotomus
Amphotericin B (AMB)
 Antifungal antibiotic
 The older and less expensive - with deoxycholate (AMB-
DOC),
 The newer and very expensive - incorporated in liposomes
(L-AMB).
 Presently, AMB is the drug with
highest cure rate in kala-azar: 99%
clinical cure
 High toxicity and need for prolonged hospitalization,
monitoring and repeated slow i.v. infusions limit its
application.
 AMB is the drug of choice in pregnant women and
breast feeding mothers.
 AMB is also useful in mucocutaneous leishmaniasis.
Miltefosine
 First orally active drug for kala-azar.
 Now is the 1st line treatment of VL
 A 4 week course of miltefosine has achieved >95% cure
rate in India and 90% in Ethiopia.
ADR:
 Anorexia, vomiting and diarrhoea
 Skin allergy
 rise in hepatic transaminases
 Reversible kidney dysfunction
 Teratogenic (It is contraindicated in pregnant women).
Sodium stibogluconate (SSG)
 Antimony compound
 It has been the standard 1st line drug for VL in most
parts of the world achieving > 90% cure rate, but is no
longer effective because of extensive resistance.
Adverse effects
 Nausea, vomiting, metallic taste, cough, pain
abdomen, pain and stiffness of injected muscle, sterile
abscesses
 Pancreatitis, liver and kidney damage,
myelosuppression
 Q-T prolongation

Used alone or in combination with paromomycin, SSG is still a 1st line drug in East Africa, Central Asia and South
America. However, response is relatively poor