Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • HIV-1 Pathophysiology/Pathogenesis:  HIV Disease Presentations

      Renal Dysfunction (continued)

      • Acute Kidney Injury (AKI)⁵

        • Factors resulting in acute kidney injury (AKI) noted in patients who are HIV negative are also seen in the HIV-infected population.⁵  

          • For example volume depletion, hypotension, or sepsis can cause acute tubular necrosis and prerenal azotemia.⁵  

            • Acute tubular necrosis damages the renal tubule cells and is a common cause of kidney failure in hospitalized patients.⁶

              • Acute Tubular Necrosis⁷

                Riaz S Acute Renal Failure, Slide Share (slide 42 of 86) http://www.slideshare.net/ShahabRiaz/acute-renal-failure-11818845

            • Opportunistic infections may be treated by nephrotoxic drugs.

            • Opportunistic infections themselves such as cytomegalovirus (CMV), candida, tuberculosis, histoplasmosis as well as a variety of drugs can result in interstitial nephritis.

              • CMV-related pathologies can include nephrocalcinosis.

              • Sometimes renal disease may be the presenting indication of HIV infection.

                • Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome is such an example.

          • Some drugs including acyclovir, atazanavir, indinavir, and sulfadiazine administration may result in crystal-induced obstructive acute kidney injury.⁵

            • Indinavir appears associated with asymptomatic crystalluria in as many as 20% of individuals.

      • Electrolyte abnormalities:

        • In hospitalized HIV-infected individuals electrolyte abnormalities may be frequently encountered.⁵ 

          • For example, up to 30%-50% of hospitalized AIDS patients exhibit hyponatremia.

          • Up to 20% of hospitalized AIDS patients may exhibit elevated serum potassium i.e. hyperkalemia.

            • Effects on electrolytes may follow from not only direct consequences of HIV infection but also from opportunistic infections along with drugs used to manage such infections including combination anti-retroviral (cART anti-HIV) medications.

            • Relationships between abnormal electrolytes and mechanisms in HIV-infected individuals have been described.⁵ 

              • Hyponatremia (low serum sodium)⁵

                • Volume depletion

                • SIADH (Syndrome of inappropriate antidiuretic hormone secretion (Schwartz-Bartter syndrome), secondary to CNS and pulmonary dysfunction.

                • Adrenal insufficiency:  reduced or absolute adrenal glucocorticoid and/or mineralocorticoid hormones⁹

              • Hypernatremia⁵

                • Volume depletion (reduced oral intake)

                • Acquired nephrogenic diabetes insipidus (medication-induced)

                  • Overview:  Diabetes insipidus may be present in patients presenting with polyuria and polydipsia (excessive urination and water ingestion). Polyuria may follow from osmotic diuresis induced by glucose, urea, mannitol or diuretics.10  Polyuria with the maximally dilute urine are consistent with nephrogenic diabetes insipidus, neurogenic diabetes insipidus and compulsive water ingestion.10   In the case of neurogenic diabetes insipidus, a pathology involving vasopressin deficiency due to alteration in the hypothalamic-pituitary-axis may be responsible.10    Vasopressin (also known as arginine vasopressin (AVP), antidiuretic hormone (ADH) regulates water retention by increasing water absorption in kidney nephron collecting ducts.11  Fvasconcellos Spacefiling model of arginine vasopressin http://commons.wikimedia.org/wiki/File:Arginine_vasopressin3d.png http://en.wikipedia.org/wiki/Vasopressin  Vasopressin is a peptide hormone which increases water permeability in the collecting duct (and distal convoluted tubule) by promoting movement of aquaporin (CD, collecting duct)-2 water channels in the kidney nephron collecting duct plasma membrane.12 Aquaporin-2 Model13 "Illustration of the topology aquaporin-2 (AQP2)" Moeller HB Olesen ETB Fenton RA Regulation of the water channel aquaporin-2 by posttranslational modification.  American Journal of Physiology- Renal Physiology 300(5), 1 May 2011. Figure above corresponds to Figure 1A in reference 13. Nephrogenic diabetes insipidus present as a result of a congenital or acquired pathology.10  For the congenital case, many mutations involving both the vasopressin (V2) receptor or aquaporin-2 water channel have been described. In comparing congenital or acquired forms, the acquired for is notably more common. Examples of acquired nephrogenic diabetes insipidus include: Polycystic kidney disease (PKD) Sickle cell anemia Chronic renal disease Obstructive uropathy10  Drug-induced acquired nephrogenic diabetes insipidus may follow administration of: Lithium Demeclocycline Amphotericin Foscarnet10

              • Hyperkalemia⁵

                • Hyperkalemia may occur as a consequence of drug administration. 

                  • Examples of drugs with this effect possibly seen in the HIV-infected population include:

                    • Pentamidine

                      • Pentamidine (NebuPent)

                        Pentamidine, an aromatic diamine, exhibits pharmacological activity against tripanasomatid protozoans and against pneumocystis jirovecii (PCP, formerly pneumocystis carinii).15  Pentamidine is considered an alternative treatment for both pulmonary and extrapulmonary disease due to pneumocystis jirovecii (P jirovecii).15 Pentamidine is also classified as a primary or secondary prophylactic agent against pneumocystosis in HIV-infected individuals or generally, in immunocompromised patients.15 In this application, pentamidine is administered by aerosol inhalant. Clinical uses of pentamidine in addition to pneumocystosis include African trypanosomiasis (sleeping sickness) and leishmaniasis.15

                    • Trimethoprim

                      • Trimethoprim (Trimpex, Proloprim, Primsol) [Structure, left; tablet (Actavis Pharma, right]

                        Trimethoprim, a diaminopyrmidine,  is an example of a bacterial dihydrofolate reductase inhibitor. Many gram-negative and gram-positive microorganisms are sensitive to this agent, although resistance to its action may occur when used alone.  Examples of typically resistant bacteria include: Pseudomonas aeruginosa Bacteriodes fragilis Enterococci.14

                • Hyporeninemic hypoaldosteronism may also be associated with elevation in K⁺.⁵ 

                  • This disorder may also be described as type IV renal tubular acidosis.¹⁶ 

                    • Hyperkalemia and acidosis present along with typically mild chronic renal disease.

                    • The pathophysiology is likely due to reduced renin production by the juxtaglomerular apparatus along with underlying renal pathology.

                      • However, the chronic kidney disease component is typically insufficient to account for the observed hyperkalemia.

                  • Reduced secretion of both K⁺ and H⁺ in the renal tubule appears responsible for the noted hyperkalemia and metabolic acidosis.¹⁶

                • Adrenal insufficiency is another potential cause of hyperkalemia.⁵

                  • Adrenal insufficiency in HIV-infected patients is typically associated with advanced disease.¹⁶ 

                    • Opportunistic infections that target the adrenal gland include:

                      • Cytomegalovirus (CMV)

                      • Disseminated Mycobacterium avium-intracellulare

                      • M tuberculosis

                      • Cryptococcus neoformans

                      • Pneumocystis jiroveci (PCP) as well as

                      • Toxoplasma gondii

                    • The adrenal gland may also be affected by neoplasms such as Kaposi's sarcoma.¹⁶ 

                  • Clinical adrenal insufficiency is generally uncommon.¹⁶ 

                    • However, more than 50% of individuals with AIDS exhibit necrotizing adrenalitis usually from cytomegalovirus infection.

                    • Necrotizing adrenalitis in this setting affects less than about 50%-70% of the adrenal gland; however, adrenal insufficiency requires typically greater than 90% gland destruction.

                  • Steroid secretion and metabolism can be altered by medications including ketoconazole which inhibits adrenal and gonadal steroid synthesis.

                    • By contrast, rifampin, phenytoin and opioids enhance steroid metabolism.¹⁶