1. Antivirus agents. Agents used in AIDs treatment. Immunomodulators

3. Antiviral Agents

4. Understanding Viruses Viral Replication A virus cannot replicate on its own. It must attach to and enter a host cell. It then uses the host cell’s energy to synthesize protein, DNA, and RNA.

5. Understanding Viruses Viruses are difficult to kill because they live inside our cells. Any drug that kills a virus may also kill our cells.

6. Viral Infections Competent immune system: Best response to viral infections A well-functioning immune system will eliminate or effectively destroy virus replication Immunocompromised patients have frequent viral infections Cancer patients, especially leukemia or lymphoma Transplant patients, due to pharmacological therapy AIDS patients, disease attacks immune system

7. Antivirals Key characteristics of antiviral drugs: Able to enter the cells infected with virus. Interfere with viral nucleic acid synthesis and/or regulation. Some agents interfere with ability of virus to bind to cells. Some agents stimulate the body’s immune system.

8. Antivirals Viruses killed by current antiviral therapy: cytomegalovirus (CMV) herpes simplex virus (HSV) human immunodeficiency virus (HIV) influenza A (the “flu”) respiratory syncytial virus (RSV)

9. Antivirals: Mechanism of Action Inhibit viral replication Inhibit viral attachment Prevent genetic copying of virus Prevent viral protein production

10. Sites of Drug Action

12. Antiviral Agents Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs

13. Antivirals Synthetic Purine Nucleoside Analogues Two types of nucleosides: Purine nucleosides guanine adenosine Pyrimidine nucleosides thymine cytosine

14. Antivirals: Purine Nucleosides AgentAntiviral Activity guanines acyclovirHSV 1 & 2, VZV ganciclovir (DHPG)CMV retinitis and systemicCMV infection ribavirin (RTCD)Influenza types A and B,RSV, LV, HV adenosines didanosine (ddl)HIV vidarabine (Ara-A)HSV, herpes zoster

15. Antivirals: Pyrimidine Nucleosides AgentAntiviral Activity cytosines lamivudine (3TC)HIV zalcitabine (ddC)HIV thymine idoxuridine (IDU)HSV stavudine (d4T)HIV trifluridineHSV zidovudine (AZT)HIV

16. Other Antivirals amantadine (Symmetrel) and rimantadine (Flumadine) influenza A foscarnet (Foscavir) CMV (retinitis and systemic) Neuraminidase Inhibitors: oseltamivir (Tamiflu) and zanamivir (Relenza) influenza types A and B

17. Antivirals: Side Effects acyclovir Burning when topically applied, nausea, vomiting, diarrhea, headache amantadine and rimantadine Anticholinergic effects, insomnia, lightheadedness, anorexia, nausea didanosine (ddl) Pancreatitis, peripheral neuropathies, seizures

18. Antivirals: Side Effects zidovudine (AZT) Bone marrow suppression, nausea, headache foscarnet (Foscavir) Headache, seizures, acute renal failure, nausea, vomiting, diarrhea ganciclovir (Cytovene) Bone marrow toxicity, nausea, anorexia, vomiting

19. Antiherpes Agents Acyclovir- prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine

20. Mechanism of Action Acyclovir an acyclic guanosine derivative Phosphorylated by viral thymidine kinase Di-and tri-phosphorylated by host cellular enzymes Inhibits viral DNA synthesis by: –1) competing with dGTP for viral DNA polymerase –2) chain termination

21. Types of allergic reactions (according to Gell and Cumbs): 1. I type reactions (anaphylactic) 2. II type reaction (humoral cytotoxic immune reactions) 3 III type reactions 4. IV type reactions 5. V type reactions (autosensibilization)

22. Classification of allergic reactions in clinic: 1. reactions of immediate type (I, II, III, V types after Cumbs) 2. reactions of delayed type (IV type after Cumbs)

23. General principles of prevention and treatment of allergic reactions 1) Avoiding contact with the allergen 2) Performing specific desensitization by repeated introduction of small doses of specific antigen 3) Performing nonspecific desensitization through administration of drugs which depress immune reactions (immune depressants) 4) Using antiallergic drugs which are able to prevent releasing the mediators of allergic reaction through stabilization of mast sells’ membranes or to block receptors with which these mediators interact in tissues 5) Symptomatic treatment of allergic reactions manifestations which have already developed

24. Directions of therapy of hypersensitivity reactions of immediate type 1) Antiallergic drugs : а) drugs which stabilize membranes of mast cells and basophiles and slow down releasing of mediators of hypersensitivity reaction (sodium-cromolin, ketotifen) б) antihistamine drugs – block receptors with which histamine binds in the tissues ( dimedrol, suprastin etc.) 2) Drugs which decrease damage of the tissues (glucocorticosteroids) 3) Drugs of symptomatic treatment (adrenalin, euphyllin)

25. Antihistamine drugs Structure of nucleus of Н1 histamine-receptors antagonists (H1 histamine-blockers) CH 2 - CH 2 - N R1R1 R1R1 CH 3

26. According to chemical structure blockers of Н 1 histamine-receptors are divided into derivatives of: 1) ethylendiamin (suprastin) 2) ethanolamin (dimedrol, klemastin) 3) piperasin (cetyrisin) 4) alkilamins (feniramin) 5) phenothiasin (diprasin, teralen) 6) oxycam (meloxycam, pyroxycam) 6) different structure (diasolin, peritol, fenkarol)

27. Comparative antiallergic activity Н 1 histamine blockers of 1st generation diprasine>tavegil>dimedrol>suprastin> fenkarol>diasoline Н 1 histamine blockers of 2nd and 3rd generations cetirizine>ebastin> terfenadine=fexofenadine> astemizole>loratadine

28. 1. Nettle-rash 2. Hay fever 3. Vasomotor rhinitis 4. Contact dermatitis 5. Angionevrotic edema 6. Serum diseases 7. Anaphylactic shock 8. Others Indications for administration of antihistamine drugs:

29. 1) Depression of CNS (disorders of coordination, increased tiredness, dizziness, diplopia, tremor, euphoria, nervousness, insomnia) 2) Disturbance of GI functioning : decreasing of appetite, nausea, vomiting, pain in epigastria, constipation of diarrhea 3) As a result of M-cholinoblocking activity – dryness of mucous membranes, eye disorders - blurred vision, impotence, ischuria, tachycardia, headache, psychosis, in case of repeated administration - tachyphylaxia Side effects of Н 1 -histamine receptors blockers of 1st generation

30. 1) Blockage Н 1 -histamine receptors 2) Stabilizing mast cells 3) Decreasing histamine secretion 4) Possessing anti-inflammatory activity Properties of Н 1 - histamine receptors blockers of 2nd and 3rd generations:

31. Advantages of Н 1 -histamine receptors blockers of 2nd and 3rd generations over classical Н 1 -antagonists 1) High specificity and affinity to Н 1 -receptors 2) Short onset 3) Long duration of action (over 24 hours) 4) Absence of blockade of other types of receptors 5) Nonpenetrable through HEB in therapeutic doses 6) Absence of tachyphylaxia

32. Anti-inflammatory drugs

33. Groups of anti-inflammatory agents and mechanism of action: 1) nonsteroidal anti-inflammatory drugs - NSAI 2) glucocorticosteroids (GCS) glucocorticosteroids LK +- Phospholipase А 2 Phospholipids Arachidonic acid Cyclic endoperoxydases Prostaglandins Thromboxan Inflammation Pain Fever Vasoconstriction Increasing of platelets aggregation - + - depressing effect - stimulating effect NSAID - Cyclooxygenases ( COG-1, COG-2, COG-3 )

34. Classification of nonsteroid anti-inflammatory drugs according to mechanism of action: I.Selective inhibitors of COG-1 (acetylsalicylic acid in small doses) II. Nonselective inhibitors of COG-1 and COG-2 (most of NSAID) III. Drugs with dominant influence on COG-2 (meloxycam, nimesulid) (meloxycam, nimesulid) IV. High selective inhibitors of COG-2 (celecoxyb, rofecoxyb) (celecoxyb, rofecoxyb)

35. Classification of nonsteroid anti- inflammatory drugs according to their chemical structure: 1) Derivatives of salicylic acid (acetylsalicylic acid) 2) Derivatives of fenamic acid - fenamates (flufenamic and mefenamic acids) 3) Derivatives of propion acid (ibuprofen, naproxen, ketoprofen, surgam) 4) Derivatives of pyrasolon (butadion) 5) Derivatives of acetic acid (dyclofenac, indometacyn, sulindac, nabumethon) 6) Derivatives of oxycam (pyroxycam, meloxycam)

36. Properties of nonsteroid anti- inflammatory drugs Anti-inflammatory action indometacyn > flurbiprofen > dyclofenac > meloxycam > nimesulid > pyroxycam > ketoprofen > naproxen >butadion > ibuprofen > acetylsalicylic acid Analgesic action Febrifugal (antipyretic) action

37. Indications for administration of nonsteroid anti-inflammatory drugs 1. Rheumatism 2. Infectious-allergic myocarditis 3. Rheumatoid polyarthritis 4. System lupus erythematosus 5. Anchilizing spondilitis (Bechterev’s disease) 6. Gout 7. Deformating osteoarthrosis (DOA) 8. Thrombophlebitis 9. Inflammation diseases of connective tissue, osseous-muscular system 10. Neuralgia 11. Meningoencephalitis 12. Chronic bronchitis 13. Virus hepatitis

38. Doses in which NSAID are used as anti- inflammatory agents DrugDay dose (g)Quantity of doses per day Acetylsalicylic acid3,0-5,03-4 Ibuprofen1,2-3,23-4 Indometacin0,075-0,153-4 Diclofenac0,075-0,152-3 Naproxen0,5-1,02 Piroxicam0,021

39. Acetylsalicylic acid

40. Aspirin С

41. Aspirin

42. Butadion

43. Indometacin (methyndol)

44. Ibuprofen (brufen)

45. Piroxicam

46. Sodium diclofenac

47. Voltaren

48. Side effects of nonsteroid anti-inflammatory drugs Gastro- intestinal tract Peptic ulcers and multiple micro-erosions Esophagitis and strictures Erosive damaging of large and small intestines Kidneya Reversible acute kidney insufficiency Water-electrolyte disorders Chronic kidney insufficiency and interstitional fibrosis Interstitioinal nephritis Nephrotic syndrome Cardio- vascular system Increasing of arterial hypertension Increasing of static cardiac insufficiency Increasing of stenocardia Liver Increasing of transaminases level Life-threatening liver insufficiency CNS Headache, Somnolence Confusion of consciousness and disorders of behavior Aseptic meningitis Blood system Thrombocytopenia Hemolytic anemia Granulocytopenia and aplastic anemia Bones, joints Disorders of cartilages and subchondral tissue OtherIncreasing of asthma and polyposis of nose, Skin rash

49. 1) Administer simultaneously with gastric protectors sucralfat, misoprostol, ranitidin, famotidin, omeprasol 2) Create and introduce NSAID which selectively inhibit COG-2 meloxycam, nimesulid Prevention of development of GI complications while administering NSAID:

50. Directions of medical treatment of rheumatoid illnesses: 1)NSAID 1)NSAID with the aim of depression of inflammatory process, pain, rigidness of muscles and joints 2) Basis drugs (disease modifying) Methotrexat, hydroxychloroquin, sulfasalazin, gold containing drugs, penicillamin,, purin derivatives (asathioprin and mercaptopurin) Alkilying drugs (chlorbutin and cyclophosphamid), cyclosporin 3) GCS 3) GCS are administered if there’s a lack of effect of NSAID and basis drugs in case of very severe currency of inflammatory process