NEVIRAPINE

Madish
Chemistry Department
TABLE OF CONTENT

■ Introduction
■ History
■ Structure
■ Preparation
■ Mechanism of action
■ Applications/Medical uses
■ Adverse effects
CLASSIFICATION OF ANTI-RETROVIRAL
DRUGS (ANTI-HIV DRUGS):
Nucleoside reverse
transcriptase Zidovudine, Stavudine, Lamivudine, Abacavir, Zalcitabine,
inhibitors (NRTIs): Emtricitabine, Didanosine.
Non-Nucleoside
reverse transcriptase Efavirenz, Nevirapine, Delaviridine.
inhibitors (NNRTIs):
Protease inhibitors
(PIs): Saquinavir, Indinavir, Nelfinavir, Amprenavir, Fosamprenavir,
Ritonavir, Lopinavir, Atazanavir.
Nucleotide reverse
transcriptase Tenofovir
inhibitors (NTRTIs):
Entry/Fusion
inhibitors: Enfuvirtide
ITRODUCTION OF NEVIRAPINE:
used to treat and
the trade
prevent HIV/AIDS
name Viramune
specifically HIV-1

Used to prevent mother

It is antiretroviral
to child spread during
medication
birth

Taken by mouth
 HISTORY:

NEVIRAPINE WAS DISCOVERED BY

HARGRAVE AT BOEHRINGER
INGELHEIM PHARMACEUTICALS
NEVIRAPINE WAS APPROVED FOR
MEDICAL USE IN THE UNITED
STATES IN 1996.
ACCORDING TO WORLD HEALTH
ORGANIZATION'S LIST OF
ESSENTIAL MEDICINES IT IS SAFE
MEDICINES NEEDED IN A HEALTH
SYSTEM
AVAILABLE AS A GENERIC NEVIRAPINE WAS THE FIRST NNRTI
MEDICATION APPROVED BY THE U.S. FOOD AND
DRUG ADMINISTRATION(FDA).

WAS APPROVED ON JUNE 21, 1996 WAS ALSO APPROVED IN EUROPE

FOR ADULTS AND SEPTEMBER 11, IN 1997
1998 FOR CHILDREN.
 Drug Class: Non-nucleoside Reverse Transcriptase
Inhibitors

Nevirapine is always used in combination with

other HIV medicines.

IMPORTANT Nevirapine comes in three different forms:

immediate-release tablets ,oral suspension (a
INFORMATION: liquid) ,extended-release tablets.
The immediate-release tablet and liquid forms of
nevirapine are approved for use in adults and
children 15 days and older.
The extended-release tablets are for use in adults
and in children 6 years of age and older
MECHANISM OF ACTION:

NNRTIs attach to and block an

HIV enzyme called reverse transcriptase,
(an enzyme that controls the replication of
the genetic material of HIV). By blocking
reverse transcriptase (NON-COMPETITIVELY),
NNRTIs prevent HIV from multiplying and can
reduce the amount of HIV in the body BY
preventing the conversion of RNA to DNA
GENERAL
REPRESENTATION:

■ Blue color-------RT active

domain
■ Red atoms -------- active
site
■ Pink---------- DNA
■ Yellow --------------NNRTI
drug
ROLE OF NEVIRAPINE:

HIV medicines can’t cure HIV/AIDS, but taking a

combination of HIV medicines (called an HIV treatment
regimen) every day helps people with HIV
■ Live longer,
■ Healthier lives.
■ Reduce the risk of HIV transmission
STRUCTURE:

■ Molecular Formula C15H14N4O

■ Average mass 266.298 Da
■ Monoisotopic mass 266.116760 Da
■ It is of Synthetic origin.
■ The chemical name : 11-cyclopropyl-
5,11-dihydro-4-methyl-6H-dipyrido
[3,2-b:2', 3'-e][1,4] diazepin-6-one.
■ Nevirapine is a white to off-white
crystalline powder
STRUCTURE:

■ belongs to the
dipyridodiazepinone
chemical class
■ According to Single
crystal X-ray diffraction it
has Butterfly shape
STRUCTURE:
■ The butterfly structure has a hydrophilic centre as a
‘body’ and two hydrophobic moieties representing the
wings.
■ Wing I is heteroaromatic ring
■ Wing II is phenyl or allyl substituent.
■ Functional group
Wing I has a functional group at one side of the ring
which is capable of accepting and/or donating hydrogen
bonds with the main chain of the amino acids
■ Wing II interacts through π-π interactions with a
hydrophobic pocket, formed in most part by the side
chains of aromatic amino acids.
■ Through this interaction side chains formed
FIRST METHOD OF PREPARATION:

■ produces 2-chloro-N-(2-chloro-4methyl-3-pyridinyl)-3-pyridine carboxamide

■ Which is then, reacts with cyclopropylamine in a sealed reactor to give N-(2-chloro-4-methyl-3-
pyridyl)-2(cyclopropylamino)-3-pyridine carboxamide
■ Followed by cyclization in presence of sodium hydride to produce nevirapine
 SECOND METHOD OF PREPARATION:

Poloxamer 407 were obtained from Hetero

Labs (Hyderabad, India)

MATERIALS Hydroxypropyl methylcellulose (HPMC) was

obtained from Merck India Ltd. (Mumbai)
AND METHODS:
Sodium lauryl sulphate (SLS), Poloxamer were
obtained from Hi Media Laboratories (Mumbai,
India)
Tween 80 and dichloromethane were obtained
from S. D. Fine-Chem. Ltd. (Mumbai, India)

PVPK30 and carboxymethylcellulose were

obtained from Merck India.
 Preparation of Nanosuspensions:
Nano-suspensions were prepared using nanoedge method
■ Initially nevirapine solubility studies in various solvents were performed to select a
suitable solvent to be used in the formulation

dichlorometh
ethanoland methanol isopropanol acetone ethyl acetate
ane,

■ The solvents used were To dissolve nevirapine (a cyclo mixture and a sonicator) were
used
■ Dichloromethane chosen as the solvent (showed good solubility of 10 mg/ml)
 FIRST STEP:

Precipitation using the solvent

evaporation technique
TWO STEP
MECHANISM: SECOND STEP:

high-pressure homogenisation
 MECHANISM:
PROCEDURE OF FIRST STEP:

the drug dissolved in the solvent at room temperature.

This solution was added drop wise using a syringe needle into different volumes
of water containing different amounts of surfactant on a magnetic stirrer.

Stirring was performed at room temperature and volatile solvents were allowed
to evaporate.

Stirring was kept for 3 h leading to precipitation of nanosuspension of the drug.

Variety of nanosuspension formulations were prepared using different

surfactants .
 MECHANISM:

PROCEDURE The nanosuspension from step I was homoginised using

OF 2ND Diax 900 homogeniser (Heidolph, Germany) for 5 min
STEP:
The above prepared suspension was then subjected to
sonication for 20 min using an ultrasonicator (Probe 12 T,
Bandelin)
This suspension was then passed through high-pressure
homogenisation in for 10 cycles at 10 000 psi Using
Emulsiflex-c5 HPH
TABLE:
MECHANISM OF ACTION:
■ Nevirapine falls in the non-
nucleoside reverse transcriptase
inhibitor (NNRTI) class of
antiretrovirals.
■ Both nucleoside and non-
nucleoside RTIs inhibit the same
target.
■ The reverse transcriptase enzyme,
(an essential viral enzyme which
transcribes viral RNA into DNA)
■ Unlike nucleoside RTIs, which bind
at the polymerase active
site, NNRT.Is bind to a hydrophobic
pocket in the subdomain of p66
which is about 10 angstrom away
from the active site.
MECHANISM OF ACTION:
■ Nevirapine is not effective against
HIV-2, as the pocket of the HIV-2
reverse transcriptase has a
different structure, which confers
intrinsic resistance to the NNRTI
class
■ Esistance to nevirapine develops
rapidly if viral replication is not
completely suppressed
■ The most common mutations
observed after nevirapine
treatment are Y181C and K103N,
which are also observed with other
NNRTIs
MECHANISM OF ACTION:

■ All NNRTIs bind within the same

pocket, viral strains which are
resistant to nevirapine are usually
also resistant to the other
NNRTIs, efavirenz and delavirdine
■ Second generation NNRTIs
like rilpivirine and etravirine are
effective in treatment for HIV
strains resistant to nevirapine and
other first generation drugs in that
same class
 ■ Treatment that uses a combination of three

cART or more drugs to treat HIV infection.

Combination antiretroviral therapy stops the
virus from making copies of itself in the body
HAART

■ HAART stops the virus from making copies of itself in the body.
This may lessen the damage to the immune system caused by HIV
and may slow down the development of AIDS. It may also help
prevent transmission of HIV to others, including from mother to
child during birth.
 Has the following positive effects on HIV:

stops it from multiplying in the blood

reduces viral load, which is the number of HIV copies in the blood

increases the number of CD4 cells, which are immune cells that HIV targets, to
Antiretroviral improve immune system function

therapy slows down and prevents the development of stage 3 HIV, or AIDS

prevents transmission

reduces the severity of complications and increases survival rates

keeps virus counts low in the blood

MEDICAL USES:
• To help control HIV infection
• Decrease the amount of HIV so immune
system can work better
• Decrease the risk of spreading HIV disease to
others
• Used in (ART)
• Used in cART
Used in HAART
MEDICAL USES:

■ Nevirapine is used if the CD4 cell count in the

body is very low
■ It is also useful component of salvage
Chemothraphy
■ (when all of theraphy fails ) used in combination
with one or more PIs as well as nucleotide reverse
transcriptase inhibitor (NRTIs), especially in those
who have not previously taken an NNRTI.
Preventing mother-to-child
transmission
■ A single dose of nevirapine given to both
mother and child reduced the rate of HIV
transmission by almost 50% compared with a
very short course of zidovudine (AZT)
prophylaxis
■ A subsequent study in Thailand showed that
prophylaxis with single-dose nevirapine in
addition to zidovudine is more effective than
zidovudine alone
 AFTER TAKING NAVIRAPINE IF YOU HAVE THESE
SIGHNS

Allergy

SIDE
Liver problem

EFFECTS: Skin problem

Autoimmune disorders

Change in body shape

SIGNS OF ALLERGY:
■ Joint or muscle pain
■ Fever and Cough
■ Mouth sores,
■ Facial swelling,
■ Blistering skin rash,
■ Flu symptoms,
■ Swollen glands,
■ Feeling weak or tired,
■ Severe tingling or numbness
■ Pain or burning when you urinate,
■ Swelling in your legs feet, lips, tongue, or throat
■ Chest pain,
■ Trouble breathing
LIFE-THRETNING EFFECT ON
LIVER:
(Cause Especially in women)
■ Nausea
■ Loss of appetite
■ Upper stomach pain
■ Tiredness
■ Fever
■ Unexplained muscle pain or weakness
■ Dark urine
■ Clay-colored stools
■ Jaundice (yellowing of the skin or eyes)
LIFE-THREATNING SKIN
REACTIONS:
■ Fever
■ Sore throat
■ Swelling in your face or tongue
■ Burning in your eyes
■ Skin pain
■ Red or purple skin rash that spreads and causes
blistering and peeling
NOTE: This type of reaction is a medical emergency.
AUTOIMMUNE
DISORDER:
■ May cause by changing the way your immune
system works.
TIME PEROID:
■ Symptoms may occur within the weeks or months
AUTOIMMUNE DISORDER
(SYMPTOMS)

■ signs of a new infection—

I. fever
II. night sweats
III. swollen glands
IV. mouth sores
V. diarrhea
VI. stomach pain
VII. weight loss
AUTOIMMUNE DISORDER (SYMPTOMS)
■ NORMAL SYMPTOMS:
I. Chest pain (especially when you breathe)
II. Dry cough and Wheezing
III. Feeling short of breath
IV. Cold sores including Sores on your genital or anal area
V. Rapid heart rate
VI. Feeling anxious or irritable
VII. Weakness or prickly feeling
VIII. Problems with balance or eye movement
IX. Trouble speaking or swallowing
X. Severe lower back pain
XI. loss of bladder or bowel control
XII. Swelling in your neck or throat (enlarged thyroid)
XIII. menstrual changes,
XIV. Impotence
XV. Loss of interest in sex
 Not all possible interactions are listed here. Tell
your doctor about all your current medicines and
any you start or stop using, especially
antiviral medication to treat hepatitis C
WHAT OTHER
DRUGS WILL an antibiotic or antifungal medicine
AFFECT
NEVIRAPINE: birth control pills or hormone replacement therapy

a blood thinner (warfarin and others)

 ergot medicine (dihydroergotaminE, ergonovine
and others)
heart or blood pressure medication
WHAT OTHER
DRUGS WILL medicine to prevent organ transplant rejection

AFFECT seizure medication.

NEVIRAPINE:
This list is not complete and many other drugs
can interact with nevirapine
This includes prescription and over-the-counter
medicines, vitamins, and herbal products
THANK
You so much