antivirus agents. agents used in aids treatment. immunomodulators
TRANSCRIPT
Antivirus agents. Agents used in AIDs treatment.
Immunomodulators
Antivirus agents. Agents used in AIDs treatment.
Immunomodulators
Antiviral Agents
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.
Understanding Viruses
Viruses are difficult to kill because they liveinside our cells.
• Any drug that kills a virus may also kill our cells.
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
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.
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)
Antivirals: Mechanism of Action
Inhibit viral replication• Inhibit viral attachment• Prevent genetic copying of virus• Prevent viral protein production
Sites of Drug Action
Sites of Drug Action
Antiviral Agents• Block viral entry into the cell or must work
inside the cell
• Most agents are pyrimidine or purine nucleoside analogs
Antivirals Synthetic Purine Nucleoside
AnaloguesTwo types of nucleosides:Purine nucleosides• guanine• adenosine
Pyrimidine nucleosides• thymine• cytosine
Antivirals: Purine Nucleosides
Agent Antiviral Activity
guanines
acyclovir HSV 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
Antivirals: Pyrimidine Nucleosides
Agent Antiviral Activitycytosines
lamivudine (3TC) HIVzalcitabine (ddC) HIV
thymineidoxuridine (IDU) HSVstavudine (d4T) HIVtrifluridine HSVzidovudine (AZT) HIV
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
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
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
Antiherpes Agents
• Acyclovir- prototype• Valacyclovir• Famciclovir• Penciclovir• Trifluridine• Vidarabine
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
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 reactions4. IV type reactions 5. V type reactions (autosensibilization)
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)
General principles of prevention and treatment of allergic reactions
1) Avoiding contact with the allergen2) Performing specific desensitization by repeated introduction of small doses of specific antigen3) 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 tissues5) Symptomatic treatment of allergic reactions manifestations which have already developed
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)
Antihistamine drugs
Structure of nucleus of Н1 histamine-receptors antagonists (H1 histamine-blockers)
CH2-CH2-N
R1
R1
CH3
CH3
According to chemical structure blockers of Н1 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)
Comparative antiallergic activityComparative antiallergic activity
Н1 histamine blockers of 1st generation
diprasine>tavegil>dimedrol>suprastin>fenkarol>diasoline
Н1 histamine blockers of 2nd and 3rd generations
cetirizine>ebastin>terfenadine=fexofenadine>
astemizole>loratadine
1. 1. Nettle-rashNettle-rash2. 2. Hay feverHay fever3. 3. Vasomotor rhinitisVasomotor rhinitis4. 4. Contact dermatitisContact dermatitis5. 5. Angionevrotic edema Angionevrotic edema 6. 6. Serum diseasesSerum diseases7. 7. Anaphylactic shockAnaphylactic shock8. 8. Others Others
Indications for administration of antihistamine drugs:
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 ofSide effects of Н Н11--histamine receptors blockers histamine receptors blockers of 1st generationof 1st generation
1) Blockage Н1-histamine receptors2) Stabilizing mast cells3) Decreasing histamine secretion4) Possessing anti-inflammatory activity
Properties of Properties of НН11- - histamine receptors blockers histamine receptors blockers
of 2nd and 3rd generations:of 2nd and 3rd generations:
Advantages of Н1-histamine receptors blockers of 2nd and 3rd generations over classical Н1-antagonists
1) High specificity and affinity to Н1-receptors2) Short onset
3) Long duration of action (over 24 hours)4) Absence of blockade of other types of receptors5) Nonpenetrable through HEB in therapeutic doses
6) Absence of tachyphylaxia
Anti-inflammatory drugs
Groups of anti-inflammatory agents and mechanism of action:1) nonsteroidal anti-inflammatory drugs - NSAI2) glucocorticosteroids (GCS)
glucocorticosteroids LK+ -
PhospholipaseА2
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)
Classification of nonsteroid anti-inflammatory Classification of nonsteroid anti-inflammatory drugs according to mechanism of actiondrugs according to mechanism of action::
I.I. Selective inhibitors of COGSelective inhibitors of COG-1 (-1 (acetylsalicylic acid acetylsalicylic acid in small dosesin small doses))
II.II. Nonselective inhibitors of COGNonselective inhibitors of COG-1 -1 and COGand COG-2 -2 ((most of NSAIDmost of NSAID))
III.III. Drugs with dominant influence on COGDrugs with dominant influence on COG-2-2 ((meloxycam, nimesulidmeloxycam, nimesulid))
IV.IV. High selective inhibitors of COGHigh selective inhibitors of COG-2-2 ((celecoxyb,celecoxyb, rofecoxybrofecoxyb))
Classification of nonsteroid anti-inflammatory drugs according to their chemical structure:
1) 1) Derivatives of salicylic acid (acetylsalicylic acid)Derivatives of salicylic acid (acetylsalicylic acid) 2) 2) Derivatives of fenamic acid - fenamatesDerivatives of fenamic acid - fenamates (flufenamic (flufenamic and mefenamic acidsand mefenamic acids))3) 3) Derivatives of propion acidDerivatives of propion acid((ibuprofen, naproxen, ketoprofen, surgamibuprofen, naproxen, ketoprofen, surgam))4) 4) Derivatives of pyrasolonDerivatives of pyrasolon ( (butadionbutadion))5) 5) Derivatives of acetic acidDerivatives of acetic acid ( (dyclofenacdyclofenac, , indometacyn, indometacyn, sulindac, nabumethonsulindac, nabumethon))6) 6) Derivatives of oxycamDerivatives of oxycam ( (pyroxycam, meloxycampyroxycam, meloxycam))
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
Indications for administration ofIndications for administration ofnonsteroid anti-inflammatory drugsnonsteroid anti-inflammatory drugs
1. Rheumatism2. Infectious-allergic myocarditis3. Rheumatoid polyarthritis4. 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 system10. Neuralgia 11. Meningoencephalitis12. Chronic bronchitis13. Virus hepatitis
Doses in which NSAID are used as anti-inflammatory agents
Drug Day dose (g) Quantity of doses per day
Acetylsalicylic acid 3,0-5,0 3-4
Ibuprofen 1,2-3,2 3-4
Indometacin 0,075-0,15 3-4
Diclofenac 0,075-0,15 2-3
Naproxen 0,5-1,0 2
Piroxicam 0,02 1
Acetylsalicylic acid
Aspirin С
Aspirin
Butadion
Indometacin (methyndol)
Ibuprofen (brufen)
Piroxicam
Sodium diclofenac
Voltaren
Side effects of nonsteroid anti-inflammatory drugsGastro-intestinal tract
Peptic ulcers and multiple micro-erosions Esophagitis and stricturesErosive damaging of large and small intestines
Kidneya Reversible acute kidney insufficiencyWater-electrolyte disordersChronic kidney insufficiency and interstitional fibrosisInterstitioinal nephritisNephrotic syndrome
Cardio-vascular system
Increasing of arterial hypertensionIncreasing of static cardiac insufficiencyIncreasing of stenocardia
Liver Increasing of transaminases levelLife-threatening liver insufficiency
CNS Headache, SomnolenceConfusion of consciousness and disorders of behavior Aseptic meningitis
Blood system
ThrombocytopeniaHemolytic anemiaGranulocytopenia and aplastic anemia
Bones, joints Disorders of cartilages and subchondral tissue
Other Increasing of asthma and polyposis of nose, Skin rash
1) Administer simultaneously with gastric protectorssucralfat, 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:
Directions of medical treatment Directions of medical treatment ofof rheumatoid illnessesrheumatoid illnesses::
1)1)NSAIDNSAID with the aim of depression of inflammatory process, pain, rigidness of muscles and joints
2) 2) Basis drugsBasis drugs ((disease modifyingdisease modifying)) • Methotrexat, hydroxychloroquin, sulfasalazin, gold
containing drugs, penicillamin, ,• purin derivatives (asathioprin and mercaptopurin)• Alkilying drugs (chlorbutin and cyclophosphamid), • cyclosporin
3) 3) GCSGCS are administered if there’s a lack of effect of NSAID and basis drugs in case of very severe currency of inflammatory process