ANTI-INFLAMMATORY DRUGS -NON-STEROIDAL ANTI- INFLAMMATORY DRUGS (NSAIDS) | MECHANISM OF ACTION | SIDE EFFECTS | PHARMACOLOGY

 PROSTAGLANDIN

Unsaturated Fatty acids containing 20 carbon, also called “Eicosanoid”

Synthesis=Arachidonic acid “20 carbon fatty acid” precursor of PG(Prostaglandin) ...

Free Arachidonic acid release from Phospholipid by action of Phospholipase A2

Cyclo-Oxygenase Pathway=PG synthesized through Cyclooxygenase pathway...

Cyclooxygenase 1= responsible for Physiologic production of PG ... 

Involved in Platelet Aggregation, Gastric Cytoprotection, Homeostasis, Reproduction, Kidney

function

Cyclooxygenase 2=↑PG level in Chronic disease & Inflammation...Expressed in Brain,

Bone, Kidney....Θ by Glucocorticoid

Lipoxygenase Pathway=Lipoxygenase Act on Arachidnic acid to form 5-HPETE,

12-HPETE, 15-HPETE (HydroPeroxyEicosa TetraEnoic Acid)...Leukotriene & Lipoxin

produced involved in Asthma

Actions of PG= via Gprotein which Activate or Inhibit Adenylyl cyclase...Stimulate Phospholipase C...Activate Sec-Messenger DAG & Inositol Triphosphate

PGF2α, TXA2, LeuT involved in Platelet aggregation, Vasoconstriction....

PGI2 involved in Vasodilation, ΘAggregation

Misoprostol=PGE1 analog...Prootect Mucosal lining of stomach by NSAID...↓Gastric

acid secretion....off-label Labor induction

S.E=Black Box warning for Abortion

ILLoprost=PGI2 analog... Vasodilator in Pulmonary Hypertension, ↑O2,↑Cardiac index

S.E= Bronchospasm, Cough, Fainting

Latanoprost, Travoprost, Bimatoprost=PGF2α analog...used in Glaucoma...

Bimatoprost used in Eyelash Hypotrichosis, ↑Eyelash thickness

S.E=Color change (Brown pigmentation), Blurred vision

Alprostadil=PGE1 analog...used in Erectile Dysfunction

S.E= Priapism, Testicular pain,

Lubiprostone= PGE1 analog...used in Chronic Idiopathic Constipation...↑CI- ↑motiliity

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

ΘCOX-Enzyme... Rofecoxib, Valdecoxib withdraw from market

Aspirin=AcetylSalicylic acid ... weak organic acid

MOA= irreversibly acetylate COX....Aspirin acetylate into Salicylic acid potent

antipyretic (no effect on normal body temp), anti-inflammatory, Analgesic=block PGE2 which release His, Bradykinin

Respiratory= ↑Alveolar ventilation, ↑CO2, ↑Respiration, Alkalosis...Acidosis at toxic dose

GIT=PGE2, PGF2α mucus protector...PGI2 Θacid...Aspirin ↑acid, destroy mucus

Platelets=Antiplatelet by ΘTxA2...Endothelial cell can resynthesize COX

Kidney = maintain renal blood flow by vasoconstriction

T.E= used in Gout, Rheumatoid arthritis, Osteoarthritis, Headache, Anthralgia,

MethlySalicylate “Oilof wintergreen” used for Acne, corn...used in TIAs (Transient

Ischemic attack)

P.K= <20yr teen with Voricella OR Influenza infection avoid Aspirin ...325mg B.D for

Analgesia...3g O.D for R.A, Osteoarthritis...162-325mg for M.I...50-325mg for stroke

half life 3.5hr

S.E= Reye syndrome; “Fulminating Hepatitis, Cerebral edema”...ulcer,↑bleeding,

Hyperthermia, Bronchoconstriction,..contra with Probenecid b/c Aspirin ↓uric acid

excretion...Category D in pregnancy

Salicylism; Hyperventilation, Tinnitus (ringing in ear), Headache, dizziness

Ibuprofen=Non-selective reversible COX inhibitor...used in Patent Ductus Arteriolus

Indomethacin, Sulindac, Etodolac= Reversible, non-selective Cox inhibitor...used in

Gout, Ankylosing Spondylitis, Osteoarthritis

Piroxicam, Miloxicam= Selective Θ of COX...O.D long t1/2...At high dose non-

selective

Diclofenac, Tolmetin= Diclofenac more potent than Neproxen, Indomethacin..

Ketorolac=Potent analgesic...not >40mg in chronic pain...used in Postoperative pain

Nebumetone=used in RA, Osteoarthritis...not used in renal, hepatic impairment

Celecoxib=Selective COX-2 inhibitor...less ulcer, prolong bleeding time...O.D 11hr

t1/2

S.E= Cardiotoxicity...Contra in Volume depletion, allegic to Sulphonamide, Renal

insufficiency, severe Heart disease....Enzyme Inhibitor

Paracetamol=N-acetyl-p-aminophenol...can be used in Gout, no↑Bleeding time

P.K=hydroxylated into NAPQI(N-Acetyl-P-BenzoQuinoneImmine), react with Sulfhydryl group and cause liver damage....at normal dose, react with Glutathione , Mercapturic acid formed , non-toxic

S.E= Hepatotoxicity at toxic dose, N-AcetylCysteine used as ANTIDOTE...Alteration in Leukocyte count...Renal tubular necrosis...

DISEASE MODIFYING ANTI-RHEUMATIC AGENTS

DMARDs ↓disease, induce remission, prventfurthur reduction of joints...ACR recommend DMARD withNSAID, low dose Corticosteroid, physical therapy

Leflunomide 

Immunomodulatory agent...ΘDHODH(DiHydro-Orotate Dehydrogenase)... precursor of UMP...cell arrest of Autoimmune lymphocyte

Θ Osteoclast production....used in R.A...Contra in pregnancy

S.E

Flu-like syndrome, Alopecia, Hypokalemia, weight loss

HydroxyChloroquine

do not slow joint damage...always used with Methotrexate... ΘPhospholipase, membrane stabilization, antioxidant

Sulfasalazine 

for early R.A, used with Methotrexate & Hydroxychloroquine

D-Pencillamine

Cysteine analog...Slow bone destruction & RA...Chelating agent...

used with NSAID & Glucocorticoid...Used for Cytinurea...

S.E Aplastic anemia,nephritis

Gold salt

Prevent further injury...AURANOFIN orally available...Suppress Phagocytes, Lysosomal activity....

S.E MYELOSUPPRESSION

BIOLOGICTHERAPY IN R.A

IL-1 & TNF-α Pro-inflammatory Cytokines in R.A...

Etanercept 

Genetically engineered Human Receptor Fusion Protein...Bind to TNF-α... Block its interaction with Cell Surface TNF Receptor....

Used in Juvenile-Arthritis, Psoriatic Arthritis...B.D s/c in week, 115 t1/2, no toxicity

Infliximab

Chimeric antibody...bind to TNF-α

Adalimumab

bind to TNF-α...reduction in MMP-1(Collagenase), MMP-3(Stromelysin- 1), C-Protein Anakinra=IL-1 receptor antagonist..S.E; Neutropenia

Abatacept=human CTLA4 protein compete with CD28 to bind on CD80/CD86...ΘT-cell

proliferation

DRUGS USED FOR GOUT

Gout= ↑Uric acid in blood...deposition of Na-Urate crystals in joint & kidney Na+-Urate end product of Purine metabolism...deposition of Na-Urate,Granulocyte phagocytozed Urate crystals...generate O2, damage tissue,release Lysozyme, inflammation...↑Lactate

Treatment

uric acid 6mg/dl

1) Allopurinol Purine analog...ΘUric acid production by competitively blocking of Last

two steps of uric acid synthesis....ΘHypoxanthine→Xanthine...ΘXanthine→uric acid

by ΘXanthine Oxidase

S.E 

 Skin rash...

Alloxanthine is active metabolite

Colchicine

Plant Alkaloid...relieve only pain in Gout attack...bind to Tubulin, depolymerize it...disrupt mobility of Granulocyte

S.E

Neutropenia, Aplastic anemia, Alopecia

Febuxostat

same to Allopurinol

Probenecid & Sulfinpyrazole

URICOSURIC Agent...weak organic acid...Θ urate-anion exchanger in Proximal tubule...ΘReabsorption of uric acid

Probenecid block tubular secretion of Pencillin,↑level of pencillin...CBC count check