PGs and Eicosanoid antagonists

Remaining portion of lec

EFFECTS OF PGs

LT C4 & LTD4 BRONCHOCONSTRICTION

LTB4 CHEMOTACTIC FACTOR

PGE2 & PROSTACYCLIN VASODILATION

PGE1 & DERIVATIVES PROTECTION ON GASTRIC MUCOSA

PGE1 & PGE2 RELAX VASCULAR & OTHER SMOOTH MUSCLE

THROMBOXANE PLATELET AGGREGATION

DRUGS

PGE2 – dinoprostone, used at term before induction of labour with oxytocin

PGE1 – misoprostol, safest abortifacient and also to maintain patency of the ductus arteriosus in infants & to prevent peptic ulcers

PG12 – epoprostenol, in severe pulmonary hypertension & to prevent platelet aggregation in dialysis machines

PGE1 – alprostadil, in tx of impotence

PGF2a – latanoprost, used in glaucoma

bimatoprost, travoprost, noprostine

THERAPEUTIC EFFECTS

Obstetrics

Pediatrics

Pulmonary hypertension & dialysis

Peptic ulcer associated with NSAID use

Urology

Ophthalmology

EICOSANOID ANTAGONISTSCorticosteroids_inhibit the synthesis of COX-2

NSAIDS _inhibit cyclooxygenase and also thromboxane, prostaglandin, prostacyclin

Leukotriene antagonists_enzyme inhibitor drug, ZILEUTON and receptor blocker, ZAFIRLUKAST & MONTELUKAST_____used for ASTHMA

ANTI-INFLAMMATORY DRUGS

NSAIDS

RHEUMATOID ARTHRITIS

GOUT

The inflammatory response is complex, involving immune system and various endogenous agents like PGs, bradykinin, histamine, chemotactic factors, superoxide free radicals formed by the action of lysosomal enzymes

ANTI-INFLAMMATORY DRUGS

NSAIDS

COX-2 INHIBITORS

ACETAMINOPHEN

DRUGS FOR ARTHRITIS

DRUGS FOR GOUT

NSAIDSASPIRIN & OTHER SALICYLATE DRUGS

PROPIONIC ACID DERIVATIVES • Ibuprofen• Naproxen• Fenoprofen• Ketoprofen• Flurbiprofen• Oxaprozin

ACETIC ACID DERIVATIVES

• Indomethacin

• Sulindac

• Etodolac

OXICAM DERIVATIVES

• Piroxicam

• Meloxicam

FENAMATES• Mefenamic• meclofenamate

OTHER AGENTS• Diclofenac• Ketorolac• Tolmetin & Nabumetone• Diflunisal

COX-2 SELECTIVE NSAIDS

Celecoxib

Valdecoxib

Rofecoxib

OTHER ANALGESICS OR NON-NARCOTIC

ANALGESICS

Acetaminophen

Phenacetin

ASPIRIN

Pharmacodynamics

Effects on different organ, tissue or cells

Pharmacokinetics

Therapeutic uses

Adverse effects

Toxicity by aspirin and treatment

Prescription to medically compromised patients

NSAID

↑ Leukocyte-EndothelialInteractions

Capillary Obstruction

IschemicCell Injury

Proteases +Oxygen Radicals

Endo/EpithelialCell Injury

Mucosal Ulceration

Loss o

f PGE 2

and P

GI 2 m

edia

ted in

hibiti

on

of aci

d sec

retio

n and c

ytopro

tect

ive

effe

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Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils

MECHANISM OF ACTION OR PHARMACODYNAMICS

ANTI-INFLAMMATORY EFFECT

ANALGESICS EFFECT

ANTIPYRETIC EFFECT

ANTI-INFLAMMATORY EFFECT

Is due to the inhibition of the enzyme prostaglandin H synthase ( cyclooxygenase or COX), which converts arachidonic acid to prostaglandins and to TXA2 & prostacyclin

Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. Its an important difference b/w other NSAIDS, which reversibly inhibit COX-1 and COX-2

NSAIDS have no effect on lipoxygenase and thus do not inhibit the production of leukotrienes

ANALGESIC EFFECT

It is related to the peripheral inhibition of prostaglandin production and it may also be due to the inhibition of pain stimuli at a subcortical site

NSAIDS prevent the potentiating action of PGs on endogenous mediators of peripheral nerve stimulation (eg, bradykinin)

ANTIPYRETIC EFFECT

Its related to inhibition of the interlukin-1 & interlukin-6-induced production of PGs in the hypothalamus & the resetting of thermoregulatory system, leading to vasodilation and increased heat loss

PHARMACOKINETIC PROPERTIES

Salicylates are weak organic acids, aspirin has a pKa of 3.5

These agents are rapidly absorbed from the intestine as well as from the stomach, where low pHfavors absorption. The rate of absorption is increased with rapidly dissolving (buffered) or predissolved (effervescent) dosage forms

Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid

Half life 3-6 hrs after acute administration & chronic administration of high doses or toxic overdose increases the t1/2 to 15-30hrs – enzymes for glycine and glucuronide conjugation become saturated

Unmetabolized salicylates are excreted by the kidney

Actions of aspirin

Anti-inflammatory – inhibits inflammation in arthritis

Analgesic action – repress sensation of pain, combination of opioids and NSAIDS are effective in treating pain caused by a malignancy

Antipyretic action- anterior hypothalamic thermoregulatory centre is elevated

Effect on Respiration: triphasic 1. Low doses: uncoupling phosphorylation → ↑

CO2 → stimulates respiration. 2. Direct stimulation of respiratory center →

Hyperventilation → resp. alkalosis → renal compensation

3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

GI system PGI2 inhibits gastric acid secretion & PGE2 and

PGF2a stimulate synthesis of protective mucus in stomach and small intestine

prostanoids are not formed, resulting in increased gastric acid secretion & diminished mucus protection – epigastric distress, ulceration or hemorrhage

1. Dose dependent hepatitis2. Reye’s syndrome

Effect on platelets

Aspirin can irreversibly inhibit thromboxane production in platelets without affecting TXA2 production in the endothelial cells of the blood vessel

Platelet aggregation is reduced, producing an anticoagulant effect with a prolonged bleeding time

Actions on the kidney

Decreased synthesis of PGs can result in retention of sodium & water and may cause edema and hyperkalemia

Interstitial nephritis can also occur with all NSAIDS except aspirin

Metabolic1. Uncoupling of Oxid. Phosphorylation2. Hyperglycemia and depletion of muscle

and hepatic glycogen

THERAPEUTIC USES

1. Inflammation• NSAIDS are first-line drugs used to arrest

inflammation & the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter’s syndrome, dysmennorhea

• Bursitis & tendonitis also respond to NSAIDS

2. Analgesia-alleviate mild-moderate pain but less effective than opioids

• more effective against pain associated with integumental structures than that associated with viscera

3. Antipyresis-reduce elevated body temperature

4. Miscellaneous uses

reduces formation of thrombi

is used prophylactically to reduce recurrent transient ischemia, unstable angina, incidence of thrombosis after coronary artery bypass grafts

5. Topically to treat corns, calluses & epidermophytosis

methyly salicylate- cutaneous counterirritant in liniments

6. Chronic use of aspirin reduces the incidence of colorectal cancer

ADVERSE EFFECTSPlatelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)Acute Renal Failure in susceptible Sodium+ water retention and edemaAnalgesic nephropathyProlongation of gestation and inhibition of labor.Hypersenstivity (not immunologic but due to PG inhibition)

Hypersensivity – urticaria, bronchoconstriction or angioedema, fatal anaphylactic shock (rare)

Reye syndrome (is an often fatal, fulminating hepatitis with cerebral edema), aspirin is given during viral infections and this occurs in children instead of aspirin, given acetaminophen to reduce fever

Drug interactions• The action of anticoagulants may be

enhanced by their displacement by aspirin from binding sites on serum albumin. Aspirin displaces tolbutamide, phenytoin & others

• Antacids may alter the absorption of aspirin• Aspirin competes for tubular reabsorption

with penicillin G& prolongs its half life• Alcohol may increase GI bleeding when

taken with alcohol

Headache - timmitus - dizziness – hearing impairment – dim visionConfusion and drowzinessSweating and hyperventilationNausea, vomitingMarked acid-base disturbancesHyperpyrexiaDehydrationCardiovascular and respiratory collapse, coma convulsions and death

Aspirin Toxicity - Salicylism

Decrease absorption - activated charcoal, emetics, gastric lavage

Enhance excretion - alkalinize urine, forced diuresis, hemodialysis

Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…

Aspirin Toxicity - Treatment

OTHER NSAIDS

PROPIONIC ACID DERIVATIVES

DRUGS

• Ibuprofen

• Naproxen

• Ketoprofen anti-inflammatory

• Fenoprofen analgesic

• Flurbiprofen antipyretic activity

• oxaprozin

Used in chronic treatment of rheumatoid arthritis & osteoarthritis

Reversible inhibitors of cyclooxygenases

Well absorbed on oral administration

Bound to serum albumin

Hepatic metabolism & are excreted by the kidney

Adverse effects – GI; dyspepsia to bleeding;

CNS, headache, tinnitus, dizziness

ACETIC ACID DERIVATIVES

DRUGS

• Indomethacin anti-inflammatory

• Sulindac analgesic

• Etodolac anti-pyretic activity

•Reversibly inhibiting

Cyclooxygenase

•Generally not used to lower

fever

Indomethacin – use to treat acute gouty arthritis, ankylosing spondylitis , osteoarthritis

Sulindac – used in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis , acute gout ( less potent than indomethacin)

OXICAM DERIVATIVES

DRUGS

• Piroxicam used to treat rheumatoid

• Meloxicam arthritis, ankylosing

spondylitis, osteoarthritis

FENAMATES

DRUGS

• Mefenamic acid

• Meclofenamate

Side effects: diarrhea

hemolytic anemia

OTHER AGENTS

DICLOFENAC

• Long term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis

• More potent than indomethacin or naproxen

• Ophthalmic preparation available

• Diclofenac stimulates in synovial fluid

• Route of excretion for drug and its metabolites in urine

KETOROLAC

• Administered intramuscularly- tx of postoperative pain

• Topically for allergic conjunctivitis

• Hepatic metabolism

• Metabolites eliminated via urine

TOLMETIN & NABUMETONE

• Treating adult or juvenile rheumatoid arthritis or osteoarthritis

DIFLUNISAL

• More potent than aspirin

COX-2-SELECTIVE NSAIDsCELECOXIB

More selective for inhibition of COX-2, its time-dependent & reversible

Used for the treatment of osteoarthritis & rheumatoid arthritis

Readily absorbed

Extensively metabolized in liver by cyt P450

Excreted in the feces & urine

Half-life, 11 hrs

Adverse effects:• Abdominal pain• Diarrhea• Dyspepsia• Gastrointestinal ulcers• Chronic renal insufficiency• Severe heart disease shd be • Volume depletion avoided• Hepatic failure• Anaphylactoid reactions• CI, allergic to sulfonamides

Drug interactions

Inhibitors of CYP2C9, such as fluconazole, fluvastatin, zafirlukast, increse serum levels of celecoxib

It could elevate the level of some B-blockers, antidepressants, antipsychotic drugs

OTHER ANALGESICS

ACETAMINOPHEN

Do not cause physical dependence or tolerance

It is a substitute for aspirin to treat mild to moderate pain for selected pts who are intolerant to aspirin, with gastric complaints

Acetaminophen does not antagonize the uricosuric agent probenecid, & may be used in pts with gout who are taking that drug

Rapidly absorbed

First pass metabolism – in luminal cells of intestine & hepatocytes

Is conjugated in liver to form inactive glucuronidated or sulfated metabolites

It is hydroxylated to form N-acetylbenzoiminoquinone – a highly reactive & potentially dangerous metabolites that reacts with sulfhydryl gps

At normal doses – forming nontoxic substance

Excretion in urine

ADVERSE EFFECTS

Skin rash

Minor allergic reactions

Alterations in leukocyte count

Renal tubular necrosis & hypoglycemic coma – rare

Hepatic necrosis

DISEASE-MODIFYING ANTIRHEUMATIC AGENTS

Methotrxate

Leflunomide

Chloroquine & hydroxychloroquine

D-Penicillamine

Gold salts

Anticytokine drugs in rheumatoid arthritis

Methotrexate

Methotrexate – It is an immunopressant agent. used in rheumatoid or psoriatic arthritis, have not responded to aspirin

Adverse effects: mucosal ulceration & nausea, cytopenias, cirrhosis of liver, acute pneumonia like syndrome

Chloroquine & Hydroxychloroquine

Used in rheumatic arthritis & malaria

Mechanism uncertain- inhibiting NA synthesis, they stabilize lysosomal membranes & trap free radicals

These drugs- slow progression of erosive bone lesions & may induce remission

Adverse effects

Low doses- chemosuppression of malaria

Higher doses- GIT upset, pruritus, headaches, visual disturbances

Discoloration of nail beds & mucus memb.

Cautiously in pts with hepatic dysfunction or severe GI problems or in pts with neurologic or blood disorders

Dermatitis

Psoriasis or porphyria

LEFLUNOMIDE

Immunomodulatory agent –causes cell arrest of autoimmune lymphocytes thru its action on dihydroorotate dehydrogenase (DHODH)

Dihydroorotate dihydroorotate orotate

dehydrogenase

Orotidine 5’monophosphate UMP

Well absorbed

Extensively bound to albumin

Half-life, 14-18 hrs

Rapidly metabolized

Excretion in urine and feces

Adverse effects, headache, nausea, diarrhea, weight loss, allergic reactions-flu like syndrome, skin rash, alopecia, hypokalemia

CI: in pregnancy & women of child bearing potential

Caution in pts with liver disease

D-Penicillamine – aacid of cysteine

Used in rheumatoid arthritis

Slow progress of bone destruction & rheumatoid arthritis

Adverse effects, dermatologic problems to nephritis, aplastic anemia

Chelating agent in tx of poisoning by heavy metals & also in treating cystinuria

GOLD SALTS, gold sodium thiomalate, aurothioglucose

Taken up by macrophages & suppress phagocytosis and lysosomal enzyme activity- retards progression of bone & articular destruction

ANTICYTOKINE THERAPIES IN RHEUMATOID ARTHRITIS

Etanercept

Infliximab

Adalimumab

Anakinra

Etanercept

• Tx in rheumatoid & psoriatic arthritis

• Combination with methotrexate, more effective than alone

Infliximab

• Monoclonal antibody

• For Crohn’s disease & rheumatoid arthritis

• Used in combination with Methotrxate

• Adverse effects:

-Long term used, antibodies developed

-Infusion reactions, fever chill pruritus urticaria

-Leading to pneumonia & cellulitus

-Leukopenia, neutropenia, thrombocytopenia, pancytopenia

-Lymphoma

Adalimumab

• Tx of rheumatoid arthritis

• Recombinant monoclonal antibody –TNFa receptor site

• Reaction ,rash, headache, nausea

• Predisposed injection – pneumonia

Anakinra

• Receptor antagonists to IL-1

• Tx of rheumatoid arthritis

GOUT

DRUGS USED IN THE TREATMENT OF GOUT

Is a metabolic disorder – high levels of uric acid in the blood

Hyperuricemia results in the deposition of sodium urate crystals in tissues (kidney & joints)

Sodium urate is the end product of purine metabolism

Deposition of urate crystals initiates an inflammatory process involving infiltration of granulocytes that phagocytize urate crystals

Process generates oxygen metabolites, which damage tissue, release of lysosomal enzymes that evoke an tissues increases

Preventing deposition of urate crystals

1. Interfering with uric acid synthesis with allopurinol

2. Increasing uric acid excretion with probenecid or sulfinpyrazone

3. Inhibiting leukocyte entry into the affected joint with colchicine

4. Administration of NSAIDs

DRUGS

• Colchicine

• Allopurinol

• Uricosuric agents – Probenecid &

Sulfinpyrazone

COLCHICINETreatment of acute gouty attacks

It binds tubulin, causes depolarization. Disrupts cellular functions, mobility of granulocytes, decreasing migration into affected area

Also inhibits synthesis and release of the leukotrienes

Adverse effects: nausea, vomiting, abdominal pain, diarrhea. Chr adm; myopathy, agranulocytosis, aplastic anemia, alopecia

CI: not be used in pregnancy

Caution in pts with hepatic, renal or CV disease

ALLOPURINOL

Reduces production of uric acid by competitive inhibits – xanthine oxidase

Treatment of primary hyperuricemia of gout & secondary to other conditions, like malignancies or in renal disease

Alloxathine (oxypurinol) – xanthine oxidase inhibitor

Adverse effects; hypersensitivity reactions, nausea, diarrhea,

Drug interaction; interferes with metabolism of anti-cancer agent 6-mercaptopurine & azathioprine (immunosuppressant), requiring a reduction in dosage

Probenecid & Sulfinpyrazone

Are organic weak acids that reduce urate levels by acting at anionic transport site in the renal tubule to prevent reabsorption of uric acid

Used for chronic gout

Undergo rapid oral absorption

Inhibit excretion of other drugs (penicillin, NSAIDs, cephalosporins, methtrexate) that are actively secreted by renal tubules

Increased urinary concentration of uric acid - urolithiasis. This risk is decreased with ingestion of large volumes of fluid or alkalinization of urine with potassium citrate

Low doses of uricosuric agents & salicyltes inhibit uric acid secretion.

Aspirin is CI in gout

Adverse effects; GI disturbances, dermatiitis, blood dyscrasias (rare)

Tx – ACUTE GOUT

Excessive alcohol consumption, diet rich in purines, kidney disease

Tx – indomethacin; decrease movement of granulocytes into affected area & NSAIDs ; decrease pain and inflammation

Tx – CHRONIC GOUT

Genetic defect- increase in rate of purine synthesis, renal deficiency, lesch-nyhan syndrome, increase synthesis of uric acid with cancer chemotherapy

Tx – uricosuric drugs, allopurinol

ANTITUSSIVES

COUGH

Cough receptors, specialized stretch receptors in the trachea & bronchial tree, send vagal afferents to cough centre & trigger the cough reflex

ANTITUSSIVE AGENTS

Codeine, Hydrocodone, Hydromorphone

Dextromethorphan

Benzonatate

Diphenhydramine

Codeine, Hydrocodone, Hydromorphone

Decrease sensitivity of central cough centre to peripheral stimuli & decrease mucosal secretions

Actions occur at doses lower than those required for analgesia

Produce constipation, nausea , respiratory depression

DEXTROMETHORPHAN

L-isomer opioid

Active as an antitussive

Devoid of analgesic or addictive liability

Less constipating than codeine

BENZONATE

Glycerol derivative chemically similar to procaine

Reduces activity of peripheral cough receptors

Also reduce threshold of central cough centre

DIPHENHYDRAMINE

Antitussive activity is not mediated at H1 receptor

Acts centrally to decrease the sensitivity of cough centre to afferents

LEVOPROPOXYPHENE

Weak opioid agonist dextropropoxyphene

Sedation as a side effects

50-100mg every 4 hrs

DEXTROMETHORPHAN

Methylated derivative of levorphanol

Free of addictive properties & produces less constipation than codeine