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I. Anti-inflammatory drugs
II. Anti-allergic drugs
III. Immunomodulators
Kharkov National Medical UniversityDepartment of Pharmacology and Medical Prescription
assistant Gordiychuk D.
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Plan of lecture:
Anti-inflammatory agents Anti-allergic drugs Immunomodulators
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Inflammation Inflammation is a complex protective response of the
organism to injury caused by damaging agents. It is aimed at inactivation or removal of these agents and
promoting healing. The traditional names for signs of inflammation come from
Latin: Dolor (pain) Calor (heat)
Rubor (redness) Tumor (swelling)
Functio laesa (loss of function)
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Mediators of inflammation Prostaglandins Bradykinin Serotonin Histamine Interleukins-2 – 6, 10,
12,13 Platelet activating factor
Gamma-Interferon Tumor Necrosis Factor Transforming Growth Factor Lymphotoxin
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The role of some prostaglandins in the body
PGE 2 – vasodilation, bronchodilation, inhibition of gastric acid secretion, stimulation of gastric mucus secretion, sensitization of pain receptors to chemical and mechanical stimuli, promotion of anterior pituitary hormones release;
PGF2α - uterus contraction, bronchoconstriction, decrease in intraocular tension;
TXA2 (thromboxane), produced by platelets, - induction of platelet aggregation, vasoconstriction;
PGI 2 - inhibition of platelet aggregation, potent vasodilation;
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Cyclo-oxygenase (COX) Exists in the tissue as constitutive isoform
(COX-1). At site of inflammation, cytokines stim the
induction of the 2nd isoform (COX-2). Inhibition of COX-2 is thought to be due to
the anti-inflammatory actions of NSAIDs. Inhibition of COX-1 is responsible for their
GIT toxicity. Most currently used NSAIDs are
somewhat selective for COX-1, but selective COX-2 inhibitors are available.
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NSAIDs – nonsteroidal anti-inflammatory drugs
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1. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonselective COX inhibitors 1. Salicylates *Acetylsalicylic acid (Aspirin) * Salicylamide 2. Pyrazolone derivatives *Phenylbutazone *Metamizol (Analginum) 3. Indole derivatives *Indomethacin 4. Propionic acid derivatives *Naproxen
5. Antranilic acid derivatives
*Mephenamic acid 6. Aryl – acetic acid
derivatives *Diclophenac sodium 7. Oxicam derivatives *Piroxicam 8. Dihydropyrrolizine
carboxylic acid derivative *Ketorolac
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Selective COX inhibitors Preferential COX-2 inhibitors Nimesulide Meloxicam Nabumeton
Selective COX-2 inhibitors Celecoxib Parecoxib Rofecoxib
NB!!!These drugs cause little gastric mucosa damage, they do not inhibit platelet
aggrigation!!!
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Mechanism of action of NSAIDs(Non-Steroidal Anti-Inflammatory Drugs)
• Act by inhibiting CycloOXygenases (COX) => no PG production
– COX-1: Constitutively expressed => house-keeping function– COX-2: Induced by pro-inflammatory factors (TNFα, IL-1)– COX-3: Just recently discovered• PGs do not cause pain, but sensitize nocireceptors to
stimulation (e.g. by 5-HT, Bradykinine, capsaicin, …)• IL-1 release from activated macrophages (bacteria, etc.) induces
COX-2 in the brain =>PG E produced => affects thermoregulation => fever=> NSAIDs have anti-pyretic effects
• Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is reversible, with the exception of Aspirin) => housekeeping PGs reduced => side effects (gastrointestinal, bronchospasms,…)
• 2nd generation NSAIDs: COX-2 specific => only the inflammatory response is inhibited => fewer side effects.
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Mechanism of anti-inflammatory drugs’ action
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Pharmacological effects of NSAIDs
Anti-inflammatory Analgesic Antipyretic Antiplatelet (Aspirin) Closure of ductus arteriosus in newborn
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Clinical uses of NSAIDs 1. Pain: headache, toothache, myalgia,
backpain; 2. Fever; 3. Arthritises: rheumatiod arthritis,
osteoarthritis, gout, ankylosing spondylitis; 4. Dismenorrhoea (especially ibuprofen); 5. Unclosure of ductus arteriosus (especially
aspirin); 6. Prevention of MI, stroke, and reinfarction
(aspirin);
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Side effects of NSAIDs
1. GIT disturbances: epigastric pain, nausea, gastric peptic ulcer (especially aspirin), gastrointestinal bleeding (especially indomethacin);
2. CNS disturbances: dizziness, mental confusion, hallucination and psychosis, depression (especially indomethacin);
3. Leukopenia, agranulocytosis (indomethacin, phenylbutzone, metamizol);
4. Water and sodium retention, edema (phenylbutzone);
5. Hypersensitivity reactions 6. Reye’s syndrom, bronchospasm (aspirin)
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ContraindicationsContraindications A) Pregnancy A) Pregnancy B) Haemophilic patientsB) Haemophilic patients C) Hypersensitivity reactionsC) Hypersensitivity reactions D) Viral infections mainly in childrenD) Viral infections mainly in children E) Peptic ulcersE) Peptic ulcers
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Drugs interactionDrugs interaction
Potentiates the gastric irritant effect of Potentiates the gastric irritant effect of alcoholalcohol
Potentiates the hypoglycaemic effects of Potentiates the hypoglycaemic effects of oral hypoglycaemic drugsoral hypoglycaemic drugs
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The Salicylates - ASPIRIN Duration of action ~ 4 hr. Orally taken. Weak acid (pKa ~ 3.5); so, non-ionized in
stomach easily absorbed. Hydrolyzed by esterases in tissues and blood to
salicylate (active) and acetic acid. Most salicylate is converted in liver to H2O-sol
conjugates that are rapidly excreted by kids.
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ASPIRIN - Therapeutic Uses Antipyretic, analgesic. Anti-inflammatory: rheumatic fever, rheumatoid arthritis
(joint dis), other rheumatological diseases. High dose needed (5-8 g/day).
But many pts cannot tolerate these doses (GIT); so, proprionic acid derivatives, ibuprofen, naproxen tried first.
Prophylaxis of diseases due to platelet aggregation. Pre-eclampsia and hypertension of pregnancy (excess
TXA2).
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Propionic acid derivativesPropionic acid derivativesIBUPROFEN:IBUPROFEN: PharmacokineticsPharmacokinetics Rapidly absorbed after oral ingestion.Rapidly absorbed after oral ingestion. Half-life 1-2 hoursHalf-life 1-2 hours Highly bound to plasma proteinsHighly bound to plasma proteins Excreted through kidney as metabolites.Excreted through kidney as metabolites.
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IBUPROFENIBUPROFEN The same mechanism & pharmacological The same mechanism & pharmacological
actions of aspirin actions of aspirin ExceptExcept that it is that it is reversible inhibitor for COX enzymesreversible inhibitor for COX enzymes
More potent More potent as antiinflammatory than as antiinflammatory than aspirin!!!aspirin!!!
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ClinicalClinical usesuses
A) AnalgesicA) Analgesic B) AntipyreticB) Antipyretic C) Anti-inflammatoryC) Anti-inflammatory D)Acute gouty arthritisD)Acute gouty arthritis E) Patent ductus arteriosusE) Patent ductus arteriosus
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Preparations of IbuprofenPreparations of Ibuprofen
Oral preparations.Oral preparations. Topical cream for osteoarthritis.Topical cream for osteoarthritis. A liquid gel for rapid relief of postsurgical A liquid gel for rapid relief of postsurgical
dental pain.dental pain. Intravenous route as In patent ductus Intravenous route as In patent ductus
arteriosus arteriosus
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Adverse effectsAdverse effects 1.Gastric upset (less frequent 1.Gastric upset (less frequent
than aspirin).than aspirin). 2.Fluid retention2.Fluid retention 3.Hypersensetivity reactions3.Hypersensetivity reactions 4.Ocular disturbances4.Ocular disturbances 5.Rare hematologic effects 5.Rare hematologic effects
(agranulocytosis & aplastic (agranulocytosis & aplastic anaemia).anaemia).
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ContraindicationsContraindications
1. Peptic ulcer1. Peptic ulcer 2. Allergic patients to aspirin2. Allergic patients to aspirin 3. Kidney impairment3. Kidney impairment 4.Liver diseases4.Liver diseases 5.Pregnancy5.Pregnancy 6.Haemophilic patients6.Haemophilic patients
The concomitant administration of ibuprofen The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition of antagonizes the irrevesible platelet inhibition of ASPIRIN ASPIRIN (limit cardioprotective effect of aspirin).(limit cardioprotective effect of aspirin).
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PiroxicamPiroxicam Mechanism of actions:Mechanism of actions: A) Non-selective inhibitors to A) Non-selective inhibitors to
COX1 & COX2COX1 & COX2 B) Traps free radicalsB) Traps free radicals C) Inhibits C) Inhibits
polymorphonuclear polymorphonuclear leukocytes migrationleukocytes migration
D) Inhibits lymphocyte D) Inhibits lymphocyte function.function.
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PharmacokineticsPharmacokinetics
Well absorbed orallyWell absorbed orally Half- Life 45 hours Half- Life 45 hours Given once dailyGiven once daily
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Adverse effectsAdverse effects Less frequent gastric upset (20%).Less frequent gastric upset (20%). Dizziness.Dizziness. Tinnitus.Tinnitus. Headache.Headache. Allergy.Allergy.
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Acetic acid derivativesAcetic acid derivativesDICLOFENACDICLOFENAC
Mechanism of actionMechanism of action Non-selective inhibitor to COX1 & COX2.Non-selective inhibitor to COX1 & COX2. More potent as anti-inflammatory than More potent as anti-inflammatory than
analgesic and antipyretics.analgesic and antipyretics.
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Clinical usesClinical usesDICLOFENACDICLOFENAC
A) Any inflammatory conditionsA) Any inflammatory conditions B) Musculoskeletal painB) Musculoskeletal pain C) DysmenorrhoeaC) Dysmenorrhoea D)Acute gouty arthritisD)Acute gouty arthritis E) FeverE) Fever F) Locally to prevent or treat post opthalmic F) Locally to prevent or treat post opthalmic
inflammationinflammation G) A topical gel for solar keratosesG) A topical gel for solar keratoses
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Adverse effectsAdverse effectsDICLOFENACDICLOFENAC
Gastric upsetGastric upset Renal impairmentRenal impairment
Elevation of serum aminotransferaseElevation of serum aminotransferase Salt & water retentionSalt & water retention
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Preparations of DICLOFENACPreparations of DICLOFENAC Diclofenac with misoprostol decreases upper Diclofenac with misoprostol decreases upper
gastrointestinal ulceration,gastrointestinal ulceration, but result in diarrhea.but result in diarrhea. Diclofenac with omeprazole to prevent recurrent Diclofenac with omeprazole to prevent recurrent
bleeding.bleeding. 1% opthalmic preparation for postoperative 1% opthalmic preparation for postoperative
opthalmic inflammation.opthalmic inflammation. A topical gel 3% for solar keratoses.A topical gel 3% for solar keratoses. Rectal suppository as analgesic or for Rectal suppository as analgesic or for
postoperative nausea.postoperative nausea.
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Selective COX 2 inhibitorsSelective COX 2 inhibitors Advantages:Advantages: 1. Highly selective inhibitors to COX2 1. Highly selective inhibitors to COX2
enzyme.enzyme. 2. Potent anti-inflammatory.2. Potent anti-inflammatory. 3. Have analgesic & antipyretic3. Have analgesic & antipyretic properties.properties. 4. Highly bound to plasma proteins.4. Highly bound to plasma proteins.
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Selective Cox 2 inhibitorsSelective Cox 2 inhibitors 5. 5. Lower incidence of gastric upsetLower incidence of gastric upset.. 6. No effect on platelet aggregation (COX1).6. No effect on platelet aggregation (COX1). 7. Renal toxicities (they are not 7. Renal toxicities (they are not
recommended for patients with severe renal recommended for patients with severe renal insufficiency).insufficiency).
8. High incidence of cardiovascular 8. High incidence of cardiovascular thrombotic events with some of them as thrombotic events with some of them as ROFECOXIB.ROFECOXIB.
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Selective Cox 2 inhibitorsSelective Cox 2 inhibitors9- They are recommended in 9- They are recommended in postoperative patients undergoing bone postoperative patients undergoing bone repair.repair.
10- Also, indicated in primary familial 10- Also, indicated in primary familial adenomatous polyposis, dysmenorrhea, adenomatous polyposis, dysmenorrhea, acute gouty arthritis, acute acute gouty arthritis, acute musculoskeletal pain, ankylosing musculoskeletal pain, ankylosing spondylitis.spondylitis.
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SAIDs – steroidal anti-inflammatory drugs
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Steroidal anti-inflammatory drugs
1. Short-acting glucocorticoids (natural)
Hydrocortisone Cortisone 2. Intermediate-acting
glucocorticoids Prednisone Prednisolone Methylprednisolone Triamcinolone
3. Long-acting Betamethasone
Dexamethasone Paramethasone 4.Topically acting
glucocorticoids Beclomethasone
dipropionate
Budesonide Fluocinolone acetonide Fluocortolone
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Preparations of SAIDsDrugs Anti-inflam. Salt retaining Topical
Cortisol 1 1.0 1Cortisone 0.8 0.8 0Prednisone 4 0.8 0Prednisolone 5 0.3 4Methylpredni- solone
5 0 5
Intermediate actingTriamcinolone 5 0 5Paramethasone 10 0 -Fluoprednisolone 15 0 7
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Preparations of SAIDs
Drugs Anti-inflam. Salt retaining Topical
Long acting
Betamethasone 25-40 0 10
Dexamethasone 30 0 10
Mineralocorticoids
Fludrocortisone 10 250 10
DOCA 0 20 0
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Phospholipids
Arachidonic acids
Lipoxygenase Cycylooxygenase
LeukotrieneProstaglandins,Thromboxane,Prostacyclins.
Phospholipase A2
CorticosteroidsMECHANISM OF ACTION OF SAIDs
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Clinical uses of SAIDs
Adrenal insufficiency Arthrities Collagen diseases (systemic lupus erhymatosis, scleroderma) Bronchial asthma Severe allergic reactions Autoimmune diseases Skin diseases Ulcerative colitis, Crohn’s disease Cerebral edema Organ transplantation and skin allograft Septic shock
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Main side effects of SAIDs Susceptibility to infections
Delayed healing of wounds Osteoporosis
Growth retardation in children Peptic ulceration Cushing habitus Hyperglycaemia
Muscular weakness Psychiatric disorders Withdrawal syndrom
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ANTI-ALLERGIC DRUGS
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Allergy An allergy is a hypersensitivity disorder of the immune
system. Allergic reactions occur when a person's immune system
reacts to normally harmless substances in the environment.
A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid.
Allergy is one of four forms of hypersensitivity and is formally called type I (or immediate) hypersensitivity.
Allergic reactions are distinctive because of excessive activation of certain white blood cells - lymphocytes called B cells, whose role is production of antibodies, called Immunoglobulin E (IgE).
Mast cells are activated and release mediator of allergy (HISTAMINE) that results in an inflammatory response.
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mild/cutaneous
mild to moderate
severe/anaphylactic
erythema, urticaria, and/or itching
skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress
severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest
Clinical Symptoms Associated With Histamine
Release
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Histamine exerts its effects on many tissues and organs:
It is not a drug but is important due to its physiological and pathophysiological actions.
Therefore, drugs that inhibit its release or block its receptors have therapeutic value.
Physiological Actions of Histamine• Primary stimulant for gastric acid and pepsin
secretion (H2) (acid secretion is enhanced by gastrin and vagal stimulation)
• Has a role as a neurotransmitter (H3) (both in the CNS and peripheral sites)
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Pathophysiological Actions of Histamine
• Cellular mediator of immediate hypersensitivity reaction and acute inflammatory response
• Anaphylaxis
• Seasonal allergies
• Duodenal ulcers
• Systemic mastocytosis
• Gastrinoma (Zollinger-Ellison Syndrome)
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Pharmacological Effects of Histamine
Ranges from mild allergic symptoms to anaphylactic shock
Involves both the H1 and H2 receptorsdilatation of small blood vessels flushing
(H1)decreased TPR and BP (H1 initial response,
H2 sustained reaction) increased capillary permeability, edema (H1)
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(Oedema of Quincke, Stevence-Johnson syndrome)
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Antiallergic drugs
1. Antihistaminics 2. Corticosteroids
3. Mast cell stabilisers 4.Antileukotriene drugs
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histaglobulin
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Histamine-related Drugs
Mast Cell Stabilizers (Cromolyn Na, Nedocromil –Tilade -, Albuterol)
H1 Receptor Antagonists (1st and 2nd generation)
H2 Receptor Antagonists (Ranitidine, Cimetidine)
H3 Receptor Agonist and Antagonists (potential new drugs being developed)
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First Generation ANTIHISTAMINE Agents
Ethanolamines: DIPHENHYDRAMINE (Benadryl) CLEMASTINE (Tavist)
Ethylenediamine:TRIPELENNAMINE
Alkylamine:CHLORPHENIRAMINE (Chlortrimeton)
Phenothiazine:PROMETHAZINE (Phenergan)
Piperazines: HYDROXYZINE (Vistaril) CYCLIZINE (Antivert)
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Uses:• Adjunctive in anaphylaxis and other cases where
histamine release can occur (H2 antagonist, and epinephrine must also be used in anaphylaxis)
• Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis)
• Sedative/sleep aid
• To prevent motion sickness (MECLIZINE, CYCLIZINE)
First Generation Agents
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First Generation AgentsAdverse Effects:
Sedation (Paradoxical Excitation in children) Dizziness Fatigue Tachydysrhythmias in overdose - rare Allergic reactions with topical use Peripheral antimuscarinic effects
• dry Mouth• blurred Vision• constipation• urinary Retention
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Drug interactions: Additive with classical antimuscarinics
Potentiate CNS depressants• opioids• sedatives• general and narcotic analgesics• alcohol
First Generation Agents
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Uses Antiallergy
Examples• CETIRIZINE (ZYRTEC)• FEXOFENADINE (ALLEGRA)• LORATADINE (CLARITIN)• DESLORATADINE (CLARINEX-
FDA APPROVED IN 2002)• LORATADINE (CLARITIN HIVES
RELIEF - FDA APPROVED IN 2004)
• AZELASTIN (INTRANASAL SPRAY)• ASTEMIZOLE• ACRIVASTINE
Second Generation Agents
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Histamine H1- AntagonistsFirst Generation:
!!!Sedating!!!
Second Generation:
!!!Non sedating!!!
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Advantages of 2nd generation antihistaminics
Higher H1 selectivity, absence of anticholinergic side effects
Absence of inhibitory action on CNS Additional antiallergic mechanisms: some of
them are acting on leukotrienes or by antiplatelet activating factor
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Mast cell stabilisers
Cromolyn sodium (Sodium cromoglycate) Nedocromil sodium Ketotifen Corticosteroids (vide supra)
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Antileukotriene drugs Montelukast Zafirlukast
Mechanism: competitive block of LT1 receptors
Clinical use: bronchial asthma
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Immunomodulators
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Thank You!!!