Transcript Antivirus agents. Agents used in AIDs treatment. Immunomodulators

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 live
inside 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
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
Analogues
Two 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
systemic
CMV infection
ribavirin (RTCD)
B,
Influenza types A and
RSV, LV, HV
adenosines
didanosine (ddl)
HIV
vidarabine (Ara-A)
HSV, herpes zoster
Antivirals: Pyrimidine
Nucleosides
Agent
cytosines
lamivudine (3TC)
zalcitabine (ddC)
thymine
idoxuridine (IDU)
stavudine (d4T)
trifluridine
zidovudine (AZT)
Antiviral Activity
HIV
HIV
HSV
HIV
HSV
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
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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 reactions
4. 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 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
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
R1
CH3
CH2-CH2-N
R1
CH3
Structure of nucleus of Н1 histamine-receptors
antagonists (H1 histamine-blockers)
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 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
Indications for administration of
antihistamine drugs:
1. Nettle-rash
2. Hay fever
3. Vasomotor rhinitis
4. Contact dermatitis
5. Angionevrotic edema
6. Serum diseases
7. Anaphylactic shock
8. Others
Side effects of Н1-histamine receptors blockers
of 1st generation
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
Properties of Н1- histamine receptors blockers
of 2nd and 3rd generations:
1) Blockage Н1-histamine receptors
2) Stabilizing mast cells
3) Decreasing histamine secretion
4) Possessing anti-inflammatory activity
Advantages of Н1-histamine receptors blockers of
2nd and 3rd generations over classical Н1-antagonists
1) High specificity and affinity to Н1-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
Anti-inflammatory drugs
Groups of anti-inflammatory agents and
mechanism of action:
1) nonsteroidal anti-inflammatory drugs - NSAI
2) glucocorticosteroids (GCS)
+
Phospholipids
glucocorticosteroids
Phospholipase
LK
А2
Arachidonic
acid
NSAID
Cyclooxygenases
(COG-1, COG-2, COG-3)
Cyclic
endoperoxydases
Prostaglandins
Inflammation
Pain
Fever
Thromboxan
Vasoconstriction
Increasing of
platelets aggregation
-
- depressing effect
+
- stimulating effect
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)
IV. High selective inhibitors of COG-2
(celecoxyb, rofecoxyb)
Classification of nonsteroid antiinflammatory 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)
Properties of nonsteroid antiinflammatory drugs
• Anti-inflammatory action
indometacyn > flurbiprofen > dyclofenac >
meloxycam > nimesulid > pyroxycam >
ketoprofen > naproxen >butadion >
ibuprofen > acetylsalicylic acid
• Analgesic action
• Febrifugal (antipyretic) action
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
Doses in which NSAID are used as antiinflammatory 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 drugs
Gastro- Peptic ulcers and multiple micro-erosions
Esophagitis and strictures
intestinal Erosive damaging of large and small intestines
tract
Kidneya Reversible acute kidney insufficiency
Water-electrolyte disorders
Chronic kidney insufficiency and interstitional fibrosis
Interstitioinal nephritis
Nephrotic syndrome
Increasing of arterial hypertension
Cardiovascular Increasing of static cardiac insufficiency
Increasing of stenocardia
system
Increasing of transaminases level
Liver
Life-threatening liver insufficiency
Headache, Somnolence
CNS
Confusion of consciousness and disorders of behavior
Aseptic meningitis
Thrombocytopenia
Blood
Hemolytic anemia
system
Granulocytopenia and aplastic anemia
Bones,
Disorders of cartilages and subchondral tissue
joints
Other
Increasing of asthma and polyposis of nose, Skin rash
Prevention of development of GI
complications while administering
NSAID:
1) Administer simultaneously with gastric
protectors
sucralfat, misoprostol, ranitidin, famotidin,
omeprasol
2) Create and introduce NSAID which
selectively inhibit COG-2
meloxycam, nimesulid
Directions of medical treatment
of rheumatoid illnesses:
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 are administered if there’s a lack of effect of NSAID
and basis drugs in case of very severe currency of
inflammatory process