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