NSC2500 - HIV-AIDS: Pathophysiology, Management, and Zidovudine

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This presentation provides a comprehensive overview of HIV-AIDS, starting with an introduction to the virus as a retroviral disease. It details the normal physiology of the immune system and how HIV disrupts it, focusing on the inactivation of Th cells (CD4+ cells) and the resulting immune deficiency. The presentation explains the process of viral replication, including the role of gp41 and gp120 proteins in infecting host cells. It then delves into the mechanism of action of antiretroviral therapy, specifically highlighting Zidovudine (AZT) as a reverse transcriptase inhibitor. The pharmacokinetics of Zidovudine are discussed, including its prodrug nature, intracellular activation, and metabolic pathways. The presentation also covers the mode of administration, side effects, contraindications, and precautions associated with Zidovudine. Finally, it explores non-pharmacological interventions, such as patient education and safe sex practices, to promote comprehensive HIV/AIDS prevention. The presentation concludes with a summary of key points and a list of references.
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Presented By:
HIV-AIDS: A Retroviral Disease
and Management
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Introduction
HIV/AIDS: Human
Immunodeficiency Virus: Acquired
Immunodeficiency Syndrome
Causative agent: Retrovirus (Punt
et al., 2019)
27,545 people resides in Australia
with HIV and 63% of this is
attributable due to sexual contact
between men (Australian
Federation of AIDS Organisations,
2017)
Other mode of transmission is
from mother (infected) to child
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Normal physiology of Immune
System
(Source: Punt et al.,
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Pathophysiology of the
Disease
AIDs virus carries their genetic information in the form of
RNA
As the virus enters the cell, RNA (2 copies) is reverse-
transcribed to c-DNA (provirus) by virally encoded enzyme
reverse transcriptase (RT) (p64)
Provirus is integrated into the host cell genome and is
replicated along with host's DNA (Th cells or CD4+ cells)
Replication leads to expression of new virons with the lyses
of the host cell
HIV-AIDS thus hamper the cell-mediated immune response
Inactivation of Th cells (CD4+) cells further hampers the
activation of humoral immune response: B-cell leading to
comprehensive loss of immunity (immunocompromised)
(Punt et al., 2019)
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The process of viral replication
AIDs virus infect human T cell leading to cell lysis
Gp41 transmembrane protein of the virion gp 120
associated with gp41 acts as a viral receptor for
CD4+ Tcells of the host
Within the viral envelop is the nucleo-capsid that
contains p17 and an inner layer of protein called p24
Once the viral genome enters the cell, the two
copies of single stranded RNA is converted t DNA by
p64 (RT) and intregrase protein p32 helps in the
insertion of the viral genome inside the host genome
(Punt et al., 2019)
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Cross-sectional schematic diagram of HIV virion
(Source: Punt et al., 2019)
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Viral Infection Pathway
(Source: Punt et al., 2019)
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The mechanism behind medication
management of HIV
The viral particles lyse the host cell
(CD4+ T cells)
The newly formed viral particles
further infects CD4+ T-cells leading
to complete destruction of the CD4+
T-cells and thereby generating
immune-deficiency
The role of anti-retro viral therapy is
to inhibit viral replication and thus
restricting the death of CD4+ T cells
and retaining immunity
(Source: Punt et al., 2019)
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Drug target
(Source: Punt et al., 2019)
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Selected drug: Zidovudine (Retrovir,
AZT)
Chemical structure of AZT
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Mode of action of Zidovudine (ZDV)
Reverse transcriptase inhibitor: nucleoside
analog
DVZ TRP inhibits the activity of HIV-1 RT
DVZ competes with natural nucleotide
counter-part of thymidine triphosphate for
incorporation inside the newly synthesized
viral DNA molecule
Incorporated inside the DNA molecule chain
leads to chain termination of DNA synthesis:
cessation of viral replication
(Punt et al., 2019)
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Pharmacokinetics: Zidovudine
(ZDV)
ZDV is a prodrug
Its enters the T-cell through passive diffusion or
through uptake receptors: Human T-lymphotropic
virus type 1 (HTLV-1)
Inside the cell its is transferred from apical to basal
compartment
In the basal compartment it is activated by
intracellular phosphorylation
Phosphorylation is done by three different
intracellular kinases
(Mazaleuskaya et al., 2015; Mu et al., 2016)
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Pharmacokinetics: Zidovudine
(ZDV)
Glucurronidation is the second metabolic pathway
that promotes inactivation of ZDV
It results in the formation of 3′-azido-3′-deoxy-5′-
D-glucopyranuronosylthymidine [5′-glucuronyl
zidovudine (GZDV)]
The inactive drug is excreted through urine in the
form of glucuronide
AZT of DVZ is also excreted by the formation of 3′-
amino-3′deoxythymidine (AMT). AMT is cytotoxic
to human body
(Chen et al., 2018)
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Pharmaco-kinetics of ZDV
(Ghodke et al.,
2012)
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Zidovudine (ZDV): Mode of
administration
Intravenous
1 mg per kg infused at a constant rate
over 1 hour every 4 hours (Mu et al., 2016)
It is also administered orally
The severity of the disease modulates the
administration of the medication
(Mu et al., 2016)
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Side-effects of ZDV
Hematological toxicity
Myopathy (Mahto et al. (2018)
Lactic acidosis, with hepatosteatosis (rare
but life-threatening mitochondrial toxicity)
(Liu et al., 2019)
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Zidovudin (ZDV): Contradiction
ZDV is not suitable for the people who are already
suffering from liver disease like jaundice or
cirrhosis of liver (Raghu & Karthikeyan, 2016)
In liver patient if administration of ZDV is
important, then regulated dosage is administered
along with administration of silibinin: hepato-
protective drug
ZDV leads to the development of Type 2 Diabetes
Mellitus (T2DM) is patients who are already
predisposed to T2DM
(Iwata & Ogawa, 2017)
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Zidovudine (ZDV):
precautions
Effective monitoring of the dosage of ZDV
based on the conditions of
Lactic acidosis of the body measured by
ADG test: Arterial Blood Gas Test
Measurement of the liver function by liver
function test
Evaluation of the blood glucose level in the
body in order to ascertain the severity of
the diabetes
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Zidovudine (ZDV): Indications
Liver damage
Disruption of mitochondrial respiration by
disruption in ATP
Cytoxicity
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Non-pharmacological interventions
for HIV/AIDS
Patient education
Having protected sex by the use of condoms
Restricted sex with multiple partners
Having sex with HIV-infected person
Prevention of the mother to child transmission by
educating infected mother not-to conceive
If conceived: treatment is given through zidovudin
and nevirapin
Patient education must be done under community
based interventions
(Landefeld et al., 2018)
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Awareness in the domain of myths
related to HIV/AIDs
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Conclusion
HIV-AIDS is a deadly disease
It causes acquired immune-deficiency
It is caused by RNA virus
The main target for RNA virus is CD4+ T-cells
It causes cell lysis and cell death (lymphocytes)
ZDV is a anti-retroviral drug for the treatment of HIV/AIDS
Drug is administered intravenously
It inhibits viral RT
However, ZDV cause hepato-toxiciy, myopathy and lactic
acidosis
In order to promote comprehensive prevention of
HIV/AIDs: patient education is important
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References
Australian Federation of AIDS Organisations (2017). HIV AIDS. Access date: 17th April 2019. Retrieved from:
https://www.afao.org.au/australia/
Chen, S., Wang, X., Zhu, H., Tang, Q., Du, W., Cao, H., ... & Lu, W. (2018). Zidovudine-Based Treatments
Inhibit the Glycosylation of ADAM17 and Reduce CD163 Shedding From Monocytes. JAIDS Journal of
Acquired Immune Deficiency Syndromes, 79(1), 126-134.
Ghodke, Y., Anderson, P. L., Sangkuhl, K., Lamba, J., Altman, R. B., & Klein, T. E. (2012). PharmGKB
summary: zidovudine pathway. Pharmacogenetics and genomics, 22(12), 891.
Iwata, K., & Ogawa, W. (2017). Reversible diabetes mellitus induced by use of, and improved after
discontinuation of, the antiretroviral medication zidovudine: a case report. Journal of medical case
reports, 11(1), 157.
Landefeld, C. C., Fomenou, L. A., Ateba, F., & Msellati, P. (2018). Prevention of Mother-to-Child Transmission
of HIV in Yaounde: Barrier to Care. AIDS care, 30(1), 116-120.
Lin, H., Stankov, M. V., Hegermann, J., Budida, R., Panayotova-Dimitrova, D., Schmidt, R. E., & Behrens, G.
M. N. (2019). Zidovudine-mediated autophagy inhibition enhances mitochondrial toxicity in muscle
cells. Antimicrobial agents and chemotherapy, 63(1), e01443-18.
Mahto, S. K., Gupta, P. K., Taneja, R. S., & Singh, A. (2018). Zidovudine-induced lactic acidosis with acute
pancreatitis and myopathy: Lethal and rare complications. Indian Journal of Pharmacology, 50(4), 212.
Mazaleuskaya, L. L., Theken, K. N., Gong, L., Thorn, C. F., FitzGerald, G. A., Altman, R. B., & Klein, T. E.
(2015). PharmGKB summary: ibuprofen pathways. Pharmacogenetics and genomics, 25(2), 96.
Mu, L., Zhou, R., Tang, F., Liu, X., Li, S., Xie, F., ... & Yu, P. (2016). Intracellular pharmacokinetic study of
zidovudine and its phosphorylated metabolites. Acta Pharmaceutica Sinica B, 6(2), 158-162.
Punt, J., Stranford, S., Jones, P. P., & Owen, J. A. (2019). Kuby immunology. WH Freeman.
Raghu, R., & Karthikeyan, S. (2016). Zidovudine and isoniazid induced liver toxicity and oxidative stress:
Evaluation of mitigating properties of silibinin. Environmental toxicology and pharmacology, 46, 217-226.
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