ABSTRACT

BS Chemistry

Madish
Hetero Chemistry

NEVIRAPINE
Anti retro viral drug
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, Emtricitabine,
inhibitors (NRTIs): 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:
• the trade name Viramune

• used to treat and prevent HIV/AIDS specifically HIV-1

• It is antiretroviral medication

• Used to prevent mother to child spread during 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 medication

• Nevirapine was the first NNRTI approved by the U.S. Food and Drug Administration(FDA).

• Was approved on June 21, 1996 for adults and September 11, 1998 for children.

• Was also approved in Europe in 1997

IMPORTANT INFORMATION:
• Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
 • Nevirapine is always used in combination with other HIV medicines.

• Nevirapine comes in three different forms: immediate-release tablets ,oral suspension (a 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

■ belongs to the dipyridodiazepinone chemical class

■ According to Single crystal X-ray diffraction it has Butterfly shape

■ 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:

MATERIALS AND METHODS:

• Poloxamer 407 were obtained from Hetero Labs (Hyderabad, India)

• Hydroxypropyl methylcellulose (HPMC) was obtained from Merck India Ltd. (Mumbai)
 • 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 formulationethanoland Methanol dichloromethane, isopropanol
acetone ethyl acetate

■ 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)

TWO STEP MECHANISM:

• FIRST STEP:

• Precipitation using the solvent evaporation technique

• 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 .

• PROCEDURE OF 2ND STEP:

• The nanosuspension from step I was homoginised using Diax 900 homogeniser
(Heidolph, Germany) for 5 min

• 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

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.

■ 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

■ 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

cART
■ Treatment that uses a combination of three 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.
Antiretroviral therapy
• 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 improve immune
system function

• 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

• 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

SIDE EFFECTS:
• AFTER TAKING NAVIRAPINE IF YOU HAVE THESE SIGHNS
 • Allergy

• Liver problem

• 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

■ 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

WHAT OTHER DRUGS WILL AFFECT NEVIRAPINE:

• 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

• an antibiotic or antifungal medicine

• birth control pills or hormone replacement therapy

• a blood thinner (warfarin and others)

• ergot medicine (dihydroergotaminE, ergonovine and others)

• heart or blood pressure medication

• medicine to prevent organ transplant rejection

• seizure medication.

• 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