ANTIviral_22.pptx pharmacology antibioti

Pharmacology antibiotic

1. Pharmacotherapy of viral hepatitis Elina Arkadyevna Korovyakova , Associate Professor of General and Clinical Pharmacology Department

2. Classification- HEPATITIS VIRUSES HAV - enterovirus ( picornavirus ), RNA , inactivated at 100 °C for 5 min, is treated symptomatically only HBV - hepadnavirus , DNA ; antigens HBsAg HBcAg , HBeAg; inactivated by boiling for 45 minutes, not sensitive to ethyl alcohol; long-term persistence - up to six months, in dry plasma - up to 25 years HCV – flavivirus , RNA ; 6 genotypes, 100 subtypes, quasi-variants HDV (delta) - RNA , defective HEV - calicium -like , RNA Outcomes: recovery, residual effects, chronic hepatitis, liver cirrhosis, primary liver cancer

3. Clinical Features of Hepatitis 1. Long incubation period (45 days - 6 months ) 2 . Gradual onset of the disease ( preicteric period lasts more than 2 weeks ) 3 . Initially COMMON: arthralgia, itchy skin and urticarial, 4. Slow onset jaundice (2 weeks or longer) and long severe icteric period, 5. Frequent exacerbations, relapses and complications (the cause may be the addition of hepatitis D ) 6 . The presence of a pronounced asthenic syndrome, prolonged post-hepatitis asthenia (sometimes up to a year or longer ) 7 . Transition to chronic hepatitis in 5-15% of cases 8 . Cirrhosis of the liver in 15-30% of patients with chronic hepatitis9. Hepatitis B - mixed. "Affectionate Killer“ 1.Mild or moderate course 2. Frequent transition to a chronic form in 50-85%, cirrhosis of the liver in 10-20% of patients with CG; hepatocellular carcinoma in 3-8% of patients with cirrhosis 3. Extrahepatic manifestations (arthritis, glomerulonephritis, neuropathy, cryoglobulinemia , autoimmune thyroiditis, thrombocytopenia, tardive cutaneous porphyria, vasculitis , Raynaud's syndrome, periarteritis nodosa , Sjögren's syndrome) - insufficiency of all external excretory glands ( dacryosialoadenopathia atrophicans ) B C

4. Classical form (“wild” - type ) HBeAg -negative form (pre/core mutant) “inactive carrier” of HBsAg does not need treatment HISTORY 1992 Interferon- α2 b (Intron A IU 3 times a week or 5 million IU daily ) 1998 Lamivudine ( Zeffix 100 mg/day) 2002 Adefovir ( Gepsera 10 mg/day) 2005 Pegylated interferon- α2 a ( Pegasys 180 mcg/week) 2005 Entecavir ( Baraclud 0.5-1 mg/day) Clinical and serological variants of chronic HBV infection requiring treatment

5. HBeAg+ monotherapy for chronic hepatitis B First line drugs : – Pegylated interferon- α ( PEG-IFN- α 2 a180 mcg/week) - Interferon- α (10 million IU 3 times a week or 5 million IU daily) Second line drugs – Lamivudine (100 mg/day) – Adefovir (10 mg/day ) – Entecavir (0.5 mg/day) 16-24 weeks Minimum 48-52 weeks Monotherapy for HBeAg-negative chronic hepatitis B First line drugs: Interferon-α (10 million IU 3 times a week or 5 million IU daily ) Second line drugs – Lamivudine (100 mg/day ) – Adefovir (10 mg/day) Minimum 48-52 weeks

6. Combined therapy for chronic hepatitis B IFN- α + Lamivudine PEG-IFN- α + Lamivudine PEG-IFN- α + Adefovir PEG-IFN- α + Entecavir Therapy for chronic hepatitis C Recombinant IFNα was approved for the treatment of hepatitis C in 1991 . Monotherapy with ribavirin in 1995 Combination therapy with IFNα and ribavirin in 1998

7. Combined Optimized therapy for chronic hepatitis C first gold standard PegIFN alfa-2a 180 mcg/week Ribavirin 1000/1200 mg =1 genotype, 800 mg =3 genotype PegIFN alfa-2v 1.5 mcg/kg Ribavirin > 10.6 mg/kg = 2, 3 genotype 13-15 mg/kg = 1 genotype 2014 - Combined Therapy for the 3 genotype with cirrhosis 5,6 genotypes with or without cirrhosis Sofosbufir or pegylated interferon + ribavirin

8. Antiviral effect: suppression of viral replication, prevention of infection of hepatocytes and transmission of antiviral activity to cells, increased sensitivity of target cells to IF-α Immunomodulatory effect: increased expression of HLA class I, increased activity of NK cells, stimulation of production of IF-α by T-lymphocytes, decreased production of antibodies, inhibition of cytochrome P450 Antitumor effect: inhibition of tumor cell growth, inhibition of oncogenes, inhibition of angiogenesis • Antiproliferative activity SIDE EFFECT Flu-like syndrome Cough Myalgia , arthralgia Headache Skin itching and rash, irritation at injection sites Hair loss, alopecia General weakness (asthenic syndrome), insomnia Interferon -α Ribavirin is an analogue of guanosine direct inhibitory effect on HCV RNA replication inhibits the activity of the host enzyme - inosine monophosphate dehydrogenase, which leads to the depletion of intracellular reserves of guanosine triphosphate and inhibition of virus replication due to a decrease in the amount of guanosine monophosphate necessary for the synthesis of viral RNA SIDE EFFECT Hemolytic anemia, Nausea Skin rash, itchingDiarrheaInsomniaShortness of breath, cough, dyspnea, pulmonary edema, atelectasis, Teratogenic and embryotoxic effects, Bradycardia, asystole

9. mechanism of action- The nucleotide prodrug forms uridine triphosphate intracellularly , which blocks RNA-dependent polymerase NS5B HCV genotype 1b,2a,3a b 4a and interrupts viral replication Pharmacokinetics and - dynamic characteristic : orally quickly absorbed and Cmax - 30 min.-2 h ., Fatty food slows down absorption, fullness increases an inactive metabolite and active uridine triphosphate are formed in the liver Excreted by the kidneys, liver and lungs sofosbuvir Sofosbuvir+ Ribavirin SIDE EFFECT Flu-like syndrome, Shortness of breath, Cough Myalgia, arthralgia Headache, insomnia, depression, General weakness (asthenic syndrome), Skin itching and rash, pruritus, irritation at injection sites Anemia Nausea, vomiting, constipation, increased bilirubin in the blood

10. Alternative treatment regimens : without cirrhosis ( 12 weeks ) daclatasfir + sofosbuvir 2. ladipasfir + sofosbuvir 3 . sofosbuvir + ribavirin1.ombitasfir + with cirrhosis (24 weeks) daclatasfir + sofosbuvir daclatasfir + sofosbuvir + ribavirin ladipasfir + sofosbuvir + ribavirin with cirrhosis ( 12- 24 weeks ) paritaprevir + ritonavir + dasabuvir + ribavirin