Anti HIV and antimycobacteial agents

1
All India Shri Shivaji Memorial society college of pharmacy,
Pune

2Outline
 Anti HIV agent -What is HIV?
-What is AIDS?
-Lifecycle of HIV
-Antiretroviral therapy
 Antimycobacterial -Introduction of mycobacteria
 Anti tubercular agent -Introduction to Tuberculosis
-Anti-tubercular agent
 Anti leprotic agent
 -What is leprosy?
-Classification of leprosy
-Antileprotic agent
 Key references

HIV(1)
H - Human. This virus infects human beings.
I - Immunodeficiency. This virus attacks a person's immune system. The
immune system is the body's defense against infections, such as bacteria
and viruses. Once attacked by HIV, the immune system becomes deficient
and doesn't work properly.
V - Virus. A virus is a type of germ too small to be seen even with a
microscope.
4
Ref: https://www.hiv.va.gov/patient/basics/what-is-HIV.asp

 HIV takes over certain immune system cells that are supposed to defend the
body. These cells are called CD4 cells, or T cells
 When HIV takes over a CD4 cell, it turns the cell into a virus factory. It
forces the cell to produce thousands of copies of the virus.
These copies then infect other CD4 cells. Infected cells don't work well and
they die early.
Over time, the loss of CD4 cells weakens the immune system, making it
harder for the body to stay healthy.
HIV is retrovirus.
A retrovirus is a single-stranded positive-sense RNA virus with a DNA
intermediate and, as an obligate parasite, targets a host cell.
5
Ref: https://www.hiv.va.gov/patient/basics/what-is-HIV.asp

Structure of HIV(6)
 HIV Capsid : HIV cores that
contain HIV RNA
 HIV envelope : Outer surface of
HIV
HIV enzymes : Protein that
carry out steps in HIV life cycle
HIV glycoprotein's : Protein
spikes embedded in HIV enevelope
HIV RNA : Genetic material
6
Ref: https://www.google.co.in/search?q=HIV+image

What is AIDS(1)
A - Acquired. This condition is acquired, meaning that a person becomes infected
with it.
I - Immuno. HIV affects a person's immune system, the part of the body that fights
off germs such as bacteria or viruses.
D - Deficiency. The immune system becomes deficient and does not work properly.
S - Syndrome. A person with AIDS may experience other diseases and infections
because of a weakened immune system.
7
Ref: https://www.hiv.va.gov/patient/basics/what-is-HIV.asp(Date of acess: 7/3/18)

 AIDS is the most advanced stage of infection caused by HIV.
 But most people who are HIV positive do not have AIDS.
 An HIV-positive person is said to have AIDS when his or her immune system
becomes so weak it can't fight off certain kinds of infections and cancers, such as
kaposi sarcoma, and memory impairment.
 Even without one of these infections, an HIV-positive person is diagnosed with
AIDS if his or her immune system weakens, as indicated by the number of CD4 cells
in his or her blood.
A CD4 cell count less than 200 in an HIV-infected person gives someone a diagnosis
of AIDS.
It can take between 2 to 10 years, or longer, for an HIV-positive person to develop
AIDS if he or she is not treated.
8
Ref: https://www.hiv.va.gov/patient/basics/what-is-HIV.asp(Date of acess : 7/3/18)

Life cycle of HIV(3)
9
 Retroviruses are unable to replicate outside of living host cells and do
not contain deoxyribonucleic acid (DNA).
The pathogenesis of HIV infection is a function of the virus life cycle,
host cellular environment, and quantity of viruses in the infected
individual.
After entering the body, the viral particle is attracted to a cell with the
appropriate CD4 receptor molecules where it attaches by fusion to a
susceptible cell membrane or by endocytosis and then enters the cell.
Ref: Edward C Klatt et al, “Pathology of HIV/AIDS”, Version 27, Mercer University, April 2016, page no. 1-118.

10
Steps in life cycle (4)
1. Binding
2. Fusion
3. Reverse transcriptase
4. Integration
5. Replication
6. Assembly
7. Budding
Ref: http://aidsinfo.nih.gov.(Date of acess: 7/3/18)

Antiretroviral therapy/treatment(5) :
11
• There are 6 classes of FDA-approved antiretroviral agents and 22 individual drugs
• Antiretroviral agents must be used in combination for effective treatment of HIV
infection
• Highly Active Antiretroviral Therapy [HAART] has led to life expectancies approaching
the general population.
Ref 5: Noga Shalev et al, “Antiretroviral Drugs in the Treatment and Prevention of HIV Infection”, page no. 1-40.

Why antiretroviral ? (8)
12
 Availability of potent ART associated with dramatic reductions in HIV-associated
morbidity and mortality
 ART can prevent HIV transmission
 Life expectancy among many HIV populations increasing
 Currently recommended ART is effective and well tolerated
 Treatment of chronic HIV infection(5)
 Prevention of mother-to-child transmission [PMTCT] (5)
 Occupational and non-occupational post-exposure prophylaxis [PEP] (5)
Ref: Benjamin Young et al, “HIV Medication and side effect”,International Association of Physicians in AIDS Care, page no. 1-30

FDA-approved Antiretroviral Classes (5)
13
1. Nucleoside reverse transcriptase inhibitors (NsRTIs)
a. Purine analogue:
1. Adenosine analogue: Tenofovir, Didanosine
2. Guanine analogue: Abacavir
b. Pyrimidine analogue:
1. Thymidine analogue: Zidovudine
2. Cytosine analogue: Lamivudine
1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
2. Protease Inhibitors (PIs)
3. Fusion inhibitor
4. CCR5 antagonist
5. Integrase inhibitor Ref 5: Noga Shalev et al, “Antiretroviral Drugs in the Treatment and Prevention of HIV Infection”, page no. 1-40.

14
Targets in antiretroviral therapy

1. Nucleoside Reverse Transcriptase Inhibitors (5,7)
(NsRTI)
15
First class of antiretrovirals developed.
•Must undergo intracellular triphosphorylation to become active against HIV
•NsRTI are the anlogue of the nucleotide
• Mechanism of action
- NRTI’s compete with host nucleotides to serve as the substrate for reverse
transcriptase chain elongation
- Absence of 3’-OH group on sugar moiety prevents the addition of another
nucleotide resulting in chain termination
- Viral DNA chain elongation is aborted and viral replication ceases

16

17

18
Example:
Tenofovir disoproxil fumarate (TDF)(8)
- Tenofovir Disoproxil Fumarate is a pro-drug,
- fumaric acid salt form of tenofovir,
- a nucleoside reverse Transcriptase inhibitor
- analog of adenosine.
• NtRTI is similar in its mechanism of action that it acts as
a DNA chain terminator
•Tenofovir contains a phosphate group and therefore only
requires diphosphorylation to become active
• Adverse effects:
nephrotoxicity, Fanconi’s syndrome, bone mineralization
disorders
Tinofovir disoproxyl fumarate

19
Zidovudine (8)
 It is a dideoxynucleoside compound in which the 3'-
hydroxy group on the sugar moiety has been replaced by an
azido group.
This modification prevents the formation of phosphodiester
linkages which are needed for the completion of nucleic acid
chains.
The compound is a potent inhibitor of HIV replication,
acting as a chain-terminator of viral DNA during reverse
transcription.
It improves immunologic function, partially reverses the
HIV-induced neurological dysfunction, and improves certain
other clinical abnormalities associated with AIDS.
Adverse effect:
 Its principal toxic effect is dose-dependent suppression of
bone marrow, resulting in anemia and leukopenia.
Zidovudine

202. Non Nucleodide reverse transcriptase inhibitor
(NNRTIs)(5)
Second class of antiretroviral agents developed
• Mechanism of action:
- NNRTI’s inhibit the HIV reverse transcriptase by binding a hydrophobic pocket close to the active site
-Lock the enzyme’s active site in an inactive conformation
-NNRTIs work in a completely different fashion, by directly binding the reverse transcriptase enzyme.
-They are NOT nucleoside analogs and are NOT incorporated into the DNA strand. NNRTIs work by non-
competitive inhibition.
• Potent but subject to rapid emergence of resistance
• Active against HIV-1 but NOT active against HIV-2

21
Mechanism of action Ref 5: Noga Shalev et al, “Antiretroviral Drugs in the Treatment and Prevention of HIV Infection”, page no. 1-40.

22
Delaviridine Mesylate
Delaviridine Mesylate (8)
- Delavirdine Mesylate is a mesylate salt form
of delavirdine, a synthetic, non-nucleoside reverse
transcriptase inhibitor. In combination with other anti-
retroviral drugs.
-This agent has been shown to reduce HIV viral load and
increase CD4 leukocyte counts in patients.
-As an inhibitor of the cytochrome P450
system, delavirdine may result in increased serum levels
of co-administered protease inhibitors metabolized by the
cytochrome P450 system.
- Delavirdine is associated with a low rate of transient
serum aminotransferase elevations during therapy and is a
rare cause of clinically apparent acute liver injury.

23
Nevirapine
Nevirapine (8)
 Nevirapine is a benzodiazepine non-nucleoside reverse transcriptase
inhibitor.
 In combination with other antiretroviral drugs, nevirapine reduces
HIV viral loads and increases CD4 counts, thereby retarding or
preventing the damage to the immune system and reducing the risk of
developing AIDS.
The mechanism of action of nevirapine is as a Non-Nucleoside
Reverse Transcriptase Inhibitor, and Cytochrome P450 3A Inducer,
and Cytochrome P450 2B6 Inducer.

NNRTI’s: Drug Interactions and Adverse Effects (5) 24
• Metabolized by CYP3A4 isoenzyme of the hepatic cytochrome p450 system
• Are either potent inducers or inhibitors of CYP3A4
• Potential for major drug interactions with HIV and non-HIV agents, including
antimycobacterials
• Adverse effects:
Rash, hepatotoxicity, neurocognitive impairment (efavirenz), teratogenicity (efavirenz)

Protease Inhibitors (PIs)(5) 25
Third class of antiretroviral agents developed
• Mechanism of action:
- Inhibit HIV protease by binding to its active site, preventing the cleavage of gag and
gag-pol precursor proteins
-Virions are produced but they are incomplete and non-infectious
• Side effects:
Abdominal upset, diarrhea, dyslipidemia, lipodystrophy, atherosclerosis

26
Mode of action

27
• HIV protease is an enzyme required for the proteolytic cleavage of viral
polyprotein precursors into individual functional proteins found in infectious
HIV. (9)
•Example,
Saquinavir Mesylate (8)
•Saquinavir is a peptide-like substrate analogue that binds to the protease active
site and inhibits the activity of the enzyme.
Saquinavir mesylate
• Saquinavir mesylate is an HIV protease inhibitor
which acts as an analog of an HIV protease cleavage
site.
• It is a highly specific inhibitor of HIV-1 and HIV-2
proteases, and also inhibits CYTOCHROME P-450
CYP3A.

28
Ritonavir (8)
 Ritonavir is a Cytochrome P450 3A Inhibitor and Protease
Inhibitor.
 The mechanism of action of ritonavir is as a HIV Protease
Inhibitor and Cytochrome P450 3A Inhibitor and
Cytochrome P450 2D6 Inhibitor and Cytochrome P450
2C19 Inducer and Cytochrome P450 3A Inducer and P-
Glycoprotein Inhibitor and Breast Cancer Resistance Protein
Inhibitor and Cytochrome P450 3A4 Inhibitor and
Cytochrome P450 1A2 Inducer and Cytochrome P450 2C9
Inducer and Cytochrome P450 2B6 Inducer and UDP
Glucuronosyltransferases Inducer.
Ritonavir

Protease Inhibitors: Drug Interactions (5) 29
• Metabolized by the CYP3A4 isoenzyme of the hepatic p450 system
• Are inhibitors of CYP3A4 to varying degrees
• Ritonavir is one of the most potent CYP3A4 inhibitors known and is used to
“boost” levels of other PI’s
• Potential for major drug interactions with numerous HIV and non-HIV drugs

Fusion inhibitors(5)
30
Fusion inhibitor prevents entry by binding to glycoprotein on the viral envelope
- Enfuvirtide T20
- Binds to the gp41 envelope glycoprotein
- Injectable only
- CCR5 antagonist prevents entry by binding to the chemokine coreceptor on the host CD4+
cell.
- Enfuvirtide is used in combination with other antiretroviral agents for the treatment of HIV-1
infection in treatment-experienced patients with evidence of HIV-1 replication despite
ongoing antiretroviral therapy.
- Enfuvirtide must be paired with at least one other antiretroviral agent that is active in vitro
according to HIV resistance tests and drug history.

31
This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell
counts in controlled studies of enfuvirtide of 24 weeks duration.
Maraviroc
- Binds to CCR5 coreceptor
- Active against CCR5 tropic virus only

32
Mode of actionRef 5: Noga Shalev et al, “Antiretroviral Drugs in the Treatment and Prevention of HIV Infection”, page no. 1-40.

Integrase inhibitor (5)
33
 Integrase is a viral enzyme that integrates retroviral DNA into the host cell genome.
 Integrase inhibitors are a new class of drugs used in the treatment of HIV.
 The first integrase inhibitor, raltegravir, was approved in 2007 and other drugs were
in clinical trials in 2011.
Mechanism of action
- Inhibits DNA strand transfer into host-cell genome and thus prevents viral integration
- Very potent in-vitro and in-vivo

34Mode of action

35•Raltegravir is a pyrrolidinone derivative and HIV INTEGRASE INHIBITOR
that is used in combination with other ANTI-HIV AGENTS for the treatment
of HIV INFECTION.
Raltegravir

Mycobacteria (10)
 Mycobacteria are immobile, slow-growing rod-shaped, gram-positive bacteria
with high genomic G+C content (61-71%).
 Due to their special staining characteristics under the microscope, which is
mediated by mycolic acid in the cell wall, they are called acid-fast.
 This is also the reason for the hardiness of mycobacteria.
 Mycobacteria can be divided into three groups:
 Mycobacterium tuberculosis complex – causative pathogen of tuberculosis
 Nontuberculous mycobacteria (NTM)
 Mycobacterium leprae – causative pathogen of leprosy
37
Ref: Ahmed Aljifri et al, “Antimycobacterial”, page no.1-30

Antimycobacterial agent (11)
38
An antimycobacterial is a type of drug used to treat mycobacteria infections.
• Types include:
1. Tuberculosis treatments
2. Leprostatic agents
Ref: Simon Tiberi et al, “Classifying new antitubercular drugs : rationale and future perspectives”, Oct 2016, page no. 181-184.

Tuberculosis (11)
 It is an infectious bacterial disease characterized by the growth of nodules
(tubercles) in the tissues, especially the lungs.
 TB is spread from person to person through the air. When people with lung TB
cough, sneeze or spit, they propel the TB germs into the air. A person needs to
inhale only a few of these germs to become infected.
 About one-third of the world's population has latent TB, which means people
have been infected by TB bacteria but are not (yet) ill with disease and cannot
transmit the disease.
39

Symptoms (11)
 chest pain, coughing up
 blood, and a
 productive, prolonged cough for more than three weeks.
 Systemic symptoms include fever, chills, nigh
 sweats, appetite loss, weight
 loss, pallor, and fatigue.
40

41Mycobacterial cell wall

Antitubercular drugs (11)
 The World Health Organization (WHO) has recently updated the classification of new anti-
tuberculosis (TB) drugs based on a meta-analysis and expert panel recommendations.
42
 In the previous WHO guidelines (2011), the choice of drugs was based on efficacy and
toxicity in a step-down manner, from group 1 to group 5.
 Group 1 included first-line drugs and groups 2–5 included second-line drugs.
 Group 5 included the drugs with (at the time) potentially limited efficacy or limited
clinical evidence.

43
WHO 2011 drug
classification
WHO 2016 drug
classification
Possible Future evolution
Group 1
First-line oral
anti-TB drugs
• Isoniazid
• Rifampicin
• Ethambutol
• Pyrazinamide
Group A
Fluoroquinolones
• Levofloxacin
• Moxifloxacin
• Gatifloxacin
Group A
Fluoroquinolones
Levofloxacin
Moxifloxacin
Gatifloxacin
Group 2
Injectable anti-
TB drugs
(injectable or
parenteral
agents)
• Streptomycin
• Kanamycin
• Amikacin
• Capreomycin
Group B
Second-line
injectable
Agents
• Amikacin
• Capreomycin
• Kanamycin
• (Streptomycin
)
Group B
Other core
second-line
agents
Bedaquiline
Delamanid
Ethionamide/[1T
D$DIF]
prothionamide
Cycloserine/[1T
D$DIF]
terizidone
Linezolid
Clofazimine

44
Group 3
Fluoroquinolo
nes
• Levofloxacin
• Moxifloxacin
• Gatifloxacin
• Ofloxacin
Group C
Other core
second-line
agents
-Ethionamide/
prothionamide
-Cycloserine/
terizidone
-Linezolid
-Clofazimine
Group C
Second-line
injectable
agents
-Amikacin
-Capreomycin
-Kanamycin
-Meropenem/
Clavulanate
Group 4
Oral
bacteriostatic
second-line
anti-TB drugs
• Ethionamide/p
rothionamide
• Cycloserine/
terizidone
• P-
Aminosalicyli
c acid
Group D
Add-on
agents
(not core
MDR-TB
regimen)
D1
• Pyrazinami
de
• Ethambutol
• High-dose
isoniazid
Group D
Add-on agents
(not core
MDR-TB
regimen
components)
• Pyrazinami
de
• Ethambutol
• High-dose
Isoniazid

45
Group 5
Anti-TB drugs
with limited
data
on efficacy
and long-term
safety in the
treatment of
drug-resistant
TB
 Linezolid
 Clofazimine
 Amoxicillin/cla
vulanate
 Imipenem/
Cilastatin
 Meropenem
 High-dose
isoniazid
 Thioacetazone,
 Clarithromycin
 D2
-Bedaquiline
-Delamanid
 D3
- p-Aminosalicylic
acid
-Imipenem
-cilastatin
-Meropenem
-Amoxicillin
-clavulanate
(Thioacetazone)
-p-
Aminosalicylic
acid
-Amoxicillin
-clavulanate
-Rifabutin

Isoniazide(10)
46
-Inhibit synthesis of mycolic acid.
-It’s a pro drug activated by by KatG.
-INH enters the bacilli by passive diffusion.
-It must be activated to become toxic to bacilli.
Essential component of all anti TB regimen (except intolerance to H or resistance)
-It is tuberculocidal , kills fast multiplying organism & inhibit slow acting organism
-Acts both on intracellular ( present in macrophages ) & extracellular bacilli
Mechanism of action
Isoniazide

47
-It became toxic by Kat G (multifunctional Catalase - peroxidase , a bacterial enzyme )
which catalyzes the product from INH an Isonicotinoyl radical that subsequently inter-
acts with mycobacterial NAD & NADP to produce dozen of adducts , one of these a
nicotinoyl NAD isomer which ↓ the activity of enoyl acyl carrier protein reductase (Inh
A) & β- ketoacyl carrier protein synthase ( Kas A) , inhibition of these enzymes↓ the
synthesis of mycolic acid an essential component of the mycobacterial cell wall &
causes cell death.

MOA of isoniazide (10)
Mycolic Acid
Arabinogalactan
Peptidoglycan
Cell membrane
R
I
B
O
S
O
M
e
Protein
Isoniazid
-
Pyrazinamide
- Mitochondria
(ATP)
- Rifampin
-
Ethambutol
-
Streptomycin
-
Cytoplasm

49
SAR(10):
1. Substitution of hydrazine portion of INH
with alkyl and aryl substitution resulted in
a series of active and inactive derivatives.
2. Substitution on the N2 position (R
1,R2=alkyl,R3=H)---- active compounds.
3. Any Substitution at N1-
hydrogen(R3=alkyl)-- ----------destroy the
activity.
4. Any Substitution--- not superior than
INH.
Isoniazide

50
Pharmacokinetics:
-Well absorbed from GIT
-Fatty food & aluminum-containing antacids may reduce absorption
-CSF penetration: 20% of plasma concentration with non-inflamed meninges
-Penetrate well into caseous material
-Excretion - urine
Metabolism
By acetylation – genetically determined
Slow acetylation – better response
t ½ - 3h
Fast acetylation – t ½ - 1h
Adverse effect : -Hepatotoxicity
-Elderly, slow acetylators more prone
-Polyneuropathy
-Prevented by concurrent pyridoxine
-Rashes, acne
-Heamatological – haemolytic anaemia in G6PD deficiency

Rifampin(10)
 Inhibits bacterial DNA-dependent RNA polymerase
 bactericidal
 Gram positive and negative
 kill intracellular organism
 -Semisynthetic derivative of Rifamycin B from Streptomyces mediterranei
 -Bactericidal to M. Tuberculosis & others –S. aureus
51
Mechanism:
-Inhibit DNA dependant RNA Synthesis (by ↓ bact RNA polymerase , selective because does not↓ mammalian
RNA polymerase )
-TB patient usually do not get primary Rifampicin resistance – If occurs is due to mutation in the repo -B gene (β
subunit of RNA polymerase ).
- No cross resistance Ref: Ahmed Aljifri et al, “Antimycobacterial”, page no.1-30

52Pharmacokinetics
-CSF penetration: 10-40% of plasma concentration with non-inflamed meninges
-Elimination hepatic, renal
Adverse effects
-Rashes, hepatotoxicity, thrombocytopenia
-Mild elevation of liver enzymes - common
-Orange discoloration of urine, sweat, tears
Potent CYP-P450 inducer- reduce the serum level of drugs
warfarin, oestrogen

Ethambutol(10)
53
Mechanism:
Inhibits arabinosyl transferases involved in cell wall biosynthesis & also interfere with mycolic acid
incorporation in mycobacterial cell wall
Bacteriostatic to M.tuberculosis
Resistance develops rapidly if used alone
 Tuberculostatic , clinically active as Streptomycin
-Fast multiplying bact.s are more sensitive
-Also act against atypical mycobacteria
-If added in triple regimen (RHZ) it is found to hasten the rate of sputum conversion & to prevent
development of resist.
Ethambutol

54SAR(10):
– Ethylene diamine chain --↑this chain length --
↓or destroy.
– Replacement of either N--↓or destroy.
– Increasing the size of Nitrogen substituents--
↓or destroy.
– Moving the location of alcohol groups--↓or
destroy. Ethambutol

55Pharmacokinetics
-Bioavailability 80%
-CSF penetration poor
-Elimination renal
Adverse effects
-Optic retro-bulbar neuritis
-Red-green colour blindness → reduced visual acuity
-Dose-related
-Reversible
-May be unilateral

Pyrazinamide ( Z) (10) 56
Chemically≡ INH
-Weak tuberculocidal more active in acidic medium
-More lethal to intracellular bacilli & to those at sites showing an inflammatory response
( Therefore effective in first two months of therapy where inflammatory changes are present )
-Good sterilizing activity
-It’s use enabled total duration of therapy to be shortened & risk of relapse to be reduced.
Mechanism ≡ INH - ↓ fatty acid synthesis but by interacting with a different fatty acid synthesis
encoding gene .

57
 PZA is thought to enter M. tub. by passive diffusion and converted to
pyrazinoic acid(its active metabolite) by bact. Pyrazinamidase enz. .
 This metabolite inhibits mycobact. Fatty acid synthase -I enz. and disrupts
mycolic acid synthesis needed for cell wall synthesis
 Mutation in the gene (pcn A) that encodes pyrazinamidase enzyme is
responsible for drug resistance ( minimized by using drug combination therapy)
Pharmacokinetics :
-Absorbed orally, widely distributed ,Good penetration in CSF.
-Metabolized in liver & excreted in urine.
-t½ -6-10 hrs
ADRs :
-Hepatotoxic -dose related
-Arthralgia , hyperuricaemia, flushing , rashes , fever & anaemia
-Loss of diabetic control
Dose – 20-30 mg /kg daily , 1500 mg if > 50 kg

Second line drugs (10):
1. Streptomycin (S):
58
 It was 1st clinically useful antibiotic drug
 It is protein synthesis inhibitor by combining with 30S ribosome
 It is tuberculocidal , but less effective than INH / Rifampicin
 Acts on extracellular bacilli only ( poor penetration in the cells )
It penetrates tubercular cavities but does not cross BBB
- Resistance when used alone (in average popul.1 in 10 to the power 8 bacilli are resistant to streptomycin –
they multiply & cause relapse therefore stopped at the earliest .)
- Atypical mycobact.s are ineffective
-Popularity ↓ due to need of IM inj. & lower margin of safety ( because of ototox. & nephrotox.).
-Dose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg

Cycloserine (Cycs) (10): 59
- Obtained from S. archidacces & is a chemical analogue of D- alanine
-↓ Bacterial cell wall synthesis
-Tuberculostatic & ↓ other G -ve organisms ( E. coli , Chlamydia)
-Resistance develop slowly , no cross resist.

60Fluoroquinolones (10)
SAR:
– Non fluorinated quinolones are inactive against mycobacteria.
– Different substitution in quinolones improve activity
toward Mycobacterium avium intracellular complex(MAC –
MAI) known as biophores.
• A cyclopropyl ring at N1position.
• F atom at position C-6 and C-8
• A C-7 heterocyclic substituents
– Excessive lipophillicity atN1 can↓activity.
– The N-7 substituents with greatest activity against
mycobacteria include substituted piperazines and
pyrrolidines

Leprosy (12)
 Leprosy is caused by acid fast bacilli called Mycobacterium leprae (M. leprae),
It is an obligate intracellular bacterium.
 It mainly affects nerves and skin. (only bacilli that can enter the nerve schwann
cell)
 Bacilli have affinity for the cooler tissues.
 Bacterium invades either dermal (cutaneous) nerves or main peripheral nerve
trunks situated superficially, in regions that are relatively cooler (face & limbs).
62
Ref: Dr. Janardhan M et al, “Pharmacotherapy of Leprosy”, Page no. 1-27

63

Classification of leprosy (12)
64
For operational purposes WHO divided leprosy into:
1. Paucibacillary leprosy (PBL) : Patient has few bacilli and is noninfectious. It
included the TT and BT types.
2. Multibacillary leprosy (MBL): Patient has large bacillary load and is infectious.
It included the LL, BL and BB types.

Anti-leprotic agent (12)
65
1. Sulfone:
Dapsone (DDS)
2. Phenazine derivative:
Clofazimine
3. Antitubercular drugs:
Rifampin,
Ethionamide
4. Other antibiotics :
Ofloxacin,
Moxifloxacin,
Minocycline,
Clarithromycin Ref: Dr. Janardhan M et al, “Pharmacotherapy of Leprosy”, Page no. 1-27

Dapsone (DDS) (12) 66
It is diamino diphenyl sulfone (DDS), the simplest, oldest,
cheapest, most active and most commonly used member of
its class.
Activity and mechanism :
 Dapsone is chemically related to sulfonamides and has the same mechanism of action, i.e.
inhibition of PABA incorporation into folic acid by folate synthase.
 The antibacterial action of dapsone is antagonized by PABA.
 It is leprostatic at very low concentrations, while growth of many other bacteria sensitive to
sulfonamides is arrested at relatively higher concentrations.

67
SAR (10):
– Relpcemnet of 1 benzene ring results in thiazosulfones— less active than DDS
– Substitution on benzene ring results in acetosulphone--↓ activity, ↓g.i.t
irritation(bz increase solubility)
– Substitution by methanesulfinate (CH2SO2)-gives sulfoxone Na, which is
water Soluble, ↓g.i.t irritation(bz increase solubility) –this drug is preferred who
can’t
tolerate DDS-but given 3times of DDS bz of its hydrolysis.
Dapsone

68
Dapsone-resistance among M. leprae, first noted in 1964, has spread and has
necessitated the use of multidrug therapy (MDT).
Pharmacokinetics:
 Dapsone is completely absorbed after oral administration and is widely
distributed in the body, though penetration in CSF is poor.
 It is 70% plasma protein bound, but more importantly it is concentrated in skin
(especially lepromatous skin), muscle, liver and kidney.
 Metabolites are excreted in bile and reabsorbed from intestine, so that ultimate
excretion occurs mostly in urine.
 The plasma t½ of dapsone is variable, though often > 24 hrs
Contraindications:
 Dapsone should not be used in patients with severe anaemia (Hb < 7 g/dl),
G-6-PD deficiency and in those showing hypersensitivity reactions.

Clofazimine (Clo) (12) 69
It is a dye with leprostatic and antiinflammatory properties.
The putative mechanisms of antileprotic action of clofazimine are:
Interference with template function of DNA in M.leprae
Alteration of membrane stucture and its transport function.
 Disruption of mitochondrial electron transport chain.
When used alone, the clinical response to clofazimine is slower than that to dapsone, and
resistance develops in 1–3 years.
Dapsone resistant M. leprae respond to clofazimine, but apparently after a lag period of
about 2 months.
Clofazimine is used as a component of multidrug therapy (MDT) of leprosy. Because of its
antiinflammatory property,
Clofazimine

70SAR (10):
– Basic nucleus –phenazine
– Halogen substitution at Pposition of two phenyls at BC-3, and C-10-enhance
activity but are not essential for activity.
– Br > Cl > CH3 >C2H5OH > H >F
Clofazimine

Rifampin (12) 71
o This important tuberculocidal drug is also the most potent cidal drug for M.leprae; rapidly
renders leprosy patients noncontagious.
o Upto 99.99% M.leprae are killed in 3–7 days by 600 mg/day dose.
o Clinical effects of rifampin are very rapid; nasal symptoms in lepromatous leprosy
subside within 2–3 weeks and skin lesions start regressing by 2 months.
o Rifampin has been included in the MDT of leprosy whereby it shortens the duration
of treatment, and no resistance develops.
Rifampin

Ofloxacin (12) 72
Many fluoroquinolones like ofloxacin, pefloxacin, moxifloxacin, sparfloxacin are highly
active against M.leprae, but ciprofloxacin has poor activity.
 It is cidal to M.leprae, and in one study, over 99.9% bacilli were found to be killed by 22
daily doses of ofloxacin monotherapy.
 However, it is not yet included in the standard treatment protocols, but can be used in
alternative regimens in case rifampin cannot be used.
Ofloxacin

Minocycline (12)
73
 Because of high lipophilicity, this tetracycline penetrates into M.leprae and is active against
them.
 A dose of 100 mg/day produces peak blood levels that exceed MIC against M. leprae by
10–20 times.
 Its antileprotic activity is less marked than that of rifampin, but greater than that of
clarithromycin.
Minocycline

Multidrug therapy (MDT) of leprosy (12) 74
 To deal with dapsone resistant strains of M. leprae and to shorten the duration of treatment
(as well as to eliminate microbial persisters, i.e. dormant forms, if possible), multidrug
therapy with rifampin, dapsone and clofazimine was introduced by the WHO in 1981.
 This was implemented under the NLEP in 1982.
The MDT is the regimen of choice for all cases of leprosy.
Its advantages are:
• Effective in cases with primary dapsone resistance.
• Prevents emergence of dapsone resistance.
• Affords quick symptom relief and renders MBL cases noncontagious within few days.
• Reduces total duration of therapy Initially under standard MDT, the PBL cases

75
Multi drug therapy
Multibacillary Paucibacillary
Rifampicin 600 mg once a month
supervised
600 mg once a month
supervised
Dapsone 100 mg daily self
administered
100 mg daily self
administered
Clofamzimine 300 mg once a month
supervised and
50 mg daily self
administered
-
Duration 12 month 6 month
Doses to be reduced suitably for children
Multidrug therapy for leprosy

76Regimen PBL MBL
Intermittent ROM R(600mg)+
Ofl(400mg)+Min(100
mg) once in monthupto
6 months
R(600mg)+Ofl(400mg
)+Min(100mg) once
in month- upto 24
months
Intermittent RMMx Mox(400mg)+Min(20
0mg)+R(600mg) once
in month-upto 6
months
Mox(400mg)+Min(20
0mg)+R(600mg) once
in month-upto 12
months
Four drug Regimen R(600mg)+Spar(200m
g)+Clar(500mg)+Min(
100mg)- 3 months
Alternative Regimen:

Conclusion (12) 77
1. Drug therapy of Leprosy started with chalmoogra oil .
2. Currently MDT therapy is advised.
3. Alternative regimens are ROM, RMMx and Four drug regimen.
4. Drug of choice in lepra reaction is corticosteroids.

78
NRTIs inhibit this process because, as the name implies, they are analogues of the natural ATGC
nucleotides that are normally used by the reverse transcriptase to build DNA. However, NRTIs lack the 3' -
OH group necessary for the next DNA base to attach. Thus, NRTIs work by competitively inhibiting
reverse-transcriptase.
NNRTIs work in a completely different fashion, by directly binding the reverse transcriptase enzyme. They
are NOT nucleoside analogs and are NOT incorporated into the DNA strand. NNRTIs work by non-
competitive inhibition.

Key References
1. https://www.hiv.va.gov/patient/basics/what-is-HIV.asp
2. Neal Nathanson, et al, “ PATHOGENESIS OF AIDS-how does HIV cause AIDS?”,University of
Pennsylvania School of Medicine, page no. 1-25.
3. Edward C Klatt et al, “Pathology of HIV/AIDS”, Version 27, Mercer University, April 2016,
page no. 1-118.
4. http://aidsinfo.nih.gov.
5. Noga Shalev et al, “Antiretroviral Drugs in the Treatment and Prevention of HIV Infection”,
page no. 1-40.
6. https://www.google.co.in/search?q=HIV+image
7. McMichael et al. (2010) “The immune responses during acute HIV-1 infection: Clues for vaccine
development”, page no.11-23.
79

Key References
80
8. Benjamin Young et al, “HIV Medication and side effect”,International Association of
Physicians in AIDS Care, page no. 1-30
9. https://pubchem.ncbi.nlm.nih.gov(Date of acess: 8/3/2018)
10.Ahmed Aljifri et al, “Antimycobacterial”, page no.1-30
11.Simon Tiberi et al, “Classifying new antitubercular drugs : rationale and future perspectives”,
Oct 2016, page no. 181-184.
12.Dr. Janardhan M et al, “Pharmacotherapy of Leprosy”, Page no. 1-27.

Anti HIV and antimycobacteial agents

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Anti HIV and antimycobacteial agents

Similar to Anti HIV and antimycobacteial agents (20)

Recently uploaded

Recently uploaded (20)

Anti HIV and antimycobacteial agents