Anti-inflammatory and corticosteroid drugs (Copeland)

Question 1

How are glucocortiosteroids synthesized?

Answer 1

Glucocorticoids are steroid hormones synthesized by the adrenal cortex that are important in regulating many physiological and developmental processes.
Because of anti-inflammatory and immunosuppressant effects, they are widely used to treat a variety of disorders.

Question 2

Uses of cortiosteroids

Answer 2

to reduce inflammation (asthma, arthritis) and swelling (cerebral edema)

to suppress the immune response (systemic lupus erythematosus, Covid 19)

to reduce nausea and vomiting (as in cancer chemotherapy)

to reduce terminal pain (associated with cancer) as replacement therapy (in Addisons disease)

Question 3

examples of corticosteroids

Answer 3

•hydrocortisone •prednisolone•dexamethasone•beclomethasone •budesonide•fluticasone

Question 4

Answer 4

explanation…… to be determined. listen to lecture

Question 5

Mechanism of the inflammatory response

Answer 5

a. Normal inflammatory response

- series of events that aid our survival in response to injury

b. Mediated by a host of endogenous compounds

-histamine

-serotonin

-complement

-bradykinin

-prostaglandins

-leukotrienes

Question 6

Properties of Prostaglandins (know picture)

Answer 6

Question 7

Physiological functions of prostaglandins Pain

Answer 7

PGI₂ and PGE₂ sensitize nerve endings to bradykinin, histamine and substance P

Question 8

Physiological Functions of Prostaglandins: Inflammation

Answer 8

Inflammation: PGI₂, PGD₂ and PGE₂ are vasodilators (edema, erythema)

Question 9

Protection of the gastric mucosa

Answer 9

: PGI₂

Question 10

Maintenance of renal blood flow:

Answer 10

PGE₂

Question 11

Fever:

Answer 11

PGE₂

Question 12

Platelets:

Answer 12

PGI₂ and PGD₂ inhibit platelet aggregation

TXA₂ stimulates platelet aggregation

Question 13

Uterus and other:

Answer 13

PGD₂ contracts uterus

Other: PGE₂ keeps ductus arteriosus open following birth

Question 14

Mechanism of action of NSAIDS

Answer 14

vThe principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production, the enzymatic activities involved in prostaglandin synthesis.

vThe first enzyme in the prostaglandin synthetic pathway is prostaglandin endoperoxidesynthase, or fatty acid cyclooxygenase. This enzyme converts arachidonic acid to the unstable intermediates PGG2 and PGH2. It is now appreciated that there are two forms of cyclooxygenase, termed cyclooxygenase-1(COX-1) and cyclooxygenase-2 (COX-2).

Question 15

Mechanism of NSAIDs 2

Answer 15

ØNSAID inhibition of PG production alleviates most of the pathologic effects associated with inflammation, but it also interferes with the physiologic role of these molecules

ØConsequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse effects, particularly those caused by erosion of gastric mucosal protection

• GI bleeding

Question 16

3 Types of Cox

Answer 16

Three types of cyclooxygenase:

- COX-1 is constitutively expressed

- COX-2 is induced at sites of inflammation by inflammatory mediators

- COX-3 recently identified

Question 17

Know know this: mainly COX

Answer 17

inhibit thromboxanes, prostaglandins and prostcyclin at the same time

Question 18

Cox 1, 2,3, function

Answer 18

vCOX-1 is expressed in all tissues and serves a variety of homeostatic physiologic functions. COX-1 is responsible for the production of protective prostaglandins in the kidney and stomach, as well as the functional thromboxane of platelets.vCOX-2, Not normally found in most tissues, expressed under conditions of tissue damage and plays an active role in the inflammatory response.vCOX-3, found primarily in cerebral cortex and heart

Question 19

cox hypothesis

Answer 19

Question 20

clinical indication of NSAIDs

Answer 20

Prevent or interrupt mild to moderate pain associated with inflammatory conditions without altering consciousness (analgesic, anti-inflammatory)

Pain quality is often described as a dull ache in

• joint pain (osteoarthritis, gout)• muscle pain (myalgia)• headache (non migraine)

Reduce elevated body temperature (fever) (antipyretic)

Question 21

Pain

Answer 21

NSAIDs usually are classified as mild analgesics

A consideration of the type of pain as well as its intensity is important in the assessment of analgesic efficacy.

They are particularly effective in settings in which inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli. Pain that accompanies inflammation and tissue injury probably results from local stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia), in part a consequence of increased excitability of central neurons in the spinal cord

In general, NSAIDs do not effect the hyperalgesia or the pain caused by direct action of prostaglandins, consistent with the concept that the analgesic effects of these agents are due to inhibition of prostaglandin synthesis.

Question 22

Inflammation

Answer 22

Inflammatory responses occur in three distinct phases, each apparently mediated by different mechanisms:

an acute transient phase, characterized by local vasodilatation and increased capillary permeability;

a delayed, subacute phase, most prominently characterized by infiltration of leukocytes and phagocytic cells; and

a chronic proliferative phase, in which tissue degeneration and fibrosis occur.

Question 23

Fever

Answer 23

Regulation of body temperature requires a delicate balance between the production and loss of heat; the hypothalamus regulates the set point at which body temperature is maintained

The cytokines increase the synthesis of PGE2 in the hypothalamic area; and PGE2 increases in cyclic AMP triggers the hypothalamus to elevate body temperature by promoting increases in heat generation and decreases in heat loss.

NSAIDs suppress this response by inhibiting the synthesis of PGE2

Question 24

Shared Therapeutic Activities and Side Effects of NSAIDs

Answer 24

All NSAIDs are analgesic, antiinflammatory, and antipyretic

these drugs usually are effective only against pain of low-to-moderate intensity

NSAIDs do not change the perception of sensory modalities other than pain.

As antipyretics, NSAIDs reduce the body temperature

Question 25

chief clinical application

Answer 25

NSAIDs find their chief clinical application as anti-inflammatory agents in the treatment of musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In general, NSAIDs provide _only symptomatic relief_from the pain and inflammation associated with the disease and _does not_ arrest the progression of pathological injury to tissue during severe episodes

Question 26

**Pharmacodynamic Effects of NSAIDs** **Positive**

Answer 26

**Analgesic (0.3-0.6 g/day) -** refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache); **-** produce a mild degree of analgesia which is much less than the analgesia produced by opioid analgesics such as morphine **anti-inflammatory (3-5 g/day) -** these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disorders **antipyretic (0.3-0.6 g/day) -** reduce fever; lower elevated body temperature by their action on the hypothalamus; normal body temperature is not reduced **antiplatelet (30-100 mg/day)-** inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects

Question 27

NSAIDS vs Opioids

Answer 27

Question 28

anypyaretic: NSAIDS vs. chlorpromazine

Answer 28

Question 29

antiinflammatory: NSAIDS vs. glucocorticoids

Answer 29

Question 30

Hx of salicylic acid

Answer 30

Question 31

Apirin- Mechanism of action

Answer 31

Aspirin **covalently** modifies both COX-1 and COX-2, thus resulting in an **irreversible** inhibition of cyclooxygenase activity. In the structure of COX-1, aspirin acetylates serine 530, preventing the binding of arachidonic acid to the active site of the enzyme and thus the ability of the enzyme to make prostaglandins. In COX-2, aspirin acetylates a homologous serine at position 516.

Question 32

Aspirin: mechanism of binding to COX

Answer 32

ASA _covalently and irreversibly_ modifies both COX-1 and COX-2 by acetylating serine-530 in the active site Acetylation results in a steric block, preventing arachidonic acid from binding Note: Acetylation of COX-2 retains the COX activity although the reaction produces a different product, 15-R-HETE

Question 33

Inhibition of COX

Answer 33

**Acetylation of a key serine within the active** **site. This reaction is not reversible and is unique to aspirin. - serine 530**

Question 34

**Effect of NSAID’s on Platelet-Endothelial Interactions**

Answer 34

Platelets are especially susceptible to aspirin-mediated _irreversible inactivation_ of cyclooxygenase because they have little or no capacity for protein biosynthesis and thus cannot regenerate the cyclooxygenase enzyme. In practical terms, this means that a single dose of aspirin will inhibit the platelet cyclooxygenase for the life of the platelet (8 to 11 days); in human beings, a daily dose of aspirin as small as 40 mg is sufficient to produce this effect. * Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can produce a mild, systemic hemostatic defect by inhibiting normal platelet function. * Aspirin acetylates and permanently inactivates cyclooxygenase (COX), while nonaspirinNSAIDs reversibly block COX; thus, all of these drugs cause platelet dysfunction by inhibiting the formation of thromboxane A₂, a platelet-activating and vasoconstricting eicosanoid.

Question 35

Aspirin: anti platelet effect : adverse effect **bleeding due to longer Cox -1 inhibition in platelets than in endothelium** *(why?)*

Answer 35

Platelets have no nucleus thus cannot resynthesize COX-1 once it is inhibited by aspirin, while endothelial cells can regenerate COX-2. Net result: selective COX 1 inhibition & reduced platelet aggregation.

Question 36

**Effect of NSAID’s on Platelet-Endothelial Interactions (picture)**

Answer 36

Question 37

Absorption of Aspirin

Answer 37

Orally ingested aspirins are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable concentrations are found in plasma in less than 30 minutes; after a single dose, a peak value is reached in about 2 hours and then gradually declines.

Question 38

Distribution of Aspirin

Answer 38

After absorption, aspirin is distributed throughout most body tissues and most transcellular fluids, primarily by pH- dependent passive processes. aspirin is actively transported by a low-capacity, saturable system into the CSF across the choroid plexus. The drug readily crosses the placental barrier.

Question 39

Biotransformation and excretion of aspirin

Answer 39

The biotransformation of aspirin takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicyluricacid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide.

Question 40

Aspirin metabolic pathways

Answer 40

**- Salicylate elimination is 1^st order at low and moderate doses;** **- When total body salicylate \> 600mg (\>3.5g/d), elimination is zero order**

Question 41

Analgesia - aspirin

Answer 41

The types of pain usually relieved by aspirin are those of low intensity that arise from integumental structures rather than from viscera, especially headache, myalgia, and arthralgia. aspirins are more widely used for pain relief than are any other classes of drugs. Long-term use does not lead to tolerance or addiction, and toxicity is lower than that of opioid analgesics. aspirin alleviate pain by virtue of a peripheral action; direct effects on the CNS also may be involved.

Question 42

Side effects of aspirin

Answer 42

Gastrointestinal symptoms CNS toxicity Allergic reaction (urticaria, angioneurotic edema, aspirin asthma, occasionally anaphylactic shock) Salicylate reaction (CNS reaction) Renal damage Hematologic effects Metabolic acidosis ® stimulates medullary respiratory center ® respiratory alkalosis

Question 43

aspirin- neurological effects

Answer 43

In high doses, aspirin have toxic effects on the CNS, consisting of stimulation (including convulsions) followed by depression. Confusion, dizziness, tinnitus, high-tone deafness, delirium, psychosis, stupor, and coma may occur. The tinnitus and hearing loss caused by aspirin poisoning are due to increased labyrinthine pressure or an effect on the hair cells of the cochlea, perhaps secondary to vasoconstriction in the auditory microvasculature. aspirin induce nausea and vomiting, which result from stimulation of sites that are accessible from the cerebrospinal fluid (CSF), probably in the medullary chemoreceptor trigger zone.

Question 44

Respiration effects - Aspirin

Answer 44

aspirin stimulate respiration directly and indirectly. Full therapeutic doses of aspirin increase oxygen consumption and CO2 production (especially in skeletal muscle); these effects are a result of aspirin- induced uncoupling of oxidative phosphorylation. The increased production of CO2 stimulates respiration. Aspirin can directly stimulate the respiratory center in the medulla. This results in marked hyperventilation, characterized by an increase in depth and a pronounced increase in rate. Patients with aspirin poisoning may have prominent increases in respiratory minute volume, and respiratory alkalosis develops. A depressant effect of aspirin on the medulla appears after high doses or after prolonged exposure.

Question 45

Cadiovascular effects- aspirin

Answer 45

Ordinary therapeutic doses of aspirins have no essential direct cardiovascular actions. The peripheral vessels tend to dilate after large doses because of a direct effect on their smooth muscle. Toxic amounts depress the circulation both directly and by central vasomotor paralysis.

Question 46

GI Effects- Aspirin

Answer 46

The ingestion of aspirin may result in epigastric distress, nausea, and vomiting. aspirin also may cause gastric ulceration; exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis all have been reported in patients on high-dose therapy but also may occur even when low doses are administered. •PGs reduce H⁺ secretion and increase mucous production•Consequently, aspirin cause some degree of gastric upset due to inhibition of PG synthesis

Question 47

Hepatic and Renal Effects

Answer 47

at least two forms of hepatic injury. In one form, hepatotoxicity is dose- dependent and usually is associated with plasma concentrations that are maintained above 150 mg/ml. severe hepatic injury and encephalopathy observed in Reye's syndrome This syndrome is a rare but often fatal consequence of infection with varicella and various other viruses, especially the influenza virus. It has been proposed that aspirin and the viral illness may act to damage mitochondria ***The use of aspirins in children or adolescents with chickenpox or influenza is contraindicated.***

Question 48

Toxicity- aspirin

Answer 48

**_Symptoms and Signs_**_._ Mild chronic aspirin intoxication is termed ***salicylism**.* When fully developed, the syndrome includes headache, dizziness, ringing in the ears, difficulty in hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea. A more severe degree of aspirin intoxication is characterized by more pronounced CNS disturbances (including generalized convulsions and coma), skin eruptions, and marked alterations in acid-base balance. Fever is usually prominent

Question 49

Acute Salicylate acide poisoning

Answer 49

Accidental ingestion of a large dose by children or attempted suicide may produce » Depression of respiratory centers • Respiratory acidosis• CNS depression• Sweating• Dehydration, electrolyte imbalance• Hypotension & vasodilation• Coma• Death

Question 50

**Chronic Salicylate Toxicity**

Answer 50

Salicylism is a constellation of symptoms that occur in some patients with the chronic use of large doses of aspirin and other salicylates •Nausea•Vomiting•Headache•Tinnitus (ringing in the ears)•Hyperglycemia•Delirium

Question 51

Aspirin Toxicity- Treatment

Answer 51

**_Treatment_**. aspirin poisoning represents an acute medical emergency, and death may result despite all recommended procedures. The treatment is directed at cardiovascular and respiratory support and correction of acid-base abnormalities plus use of measures to speed excretion of aspirin. **Decrease absorption - activated charcoal, emetics, gastric lavage** **Enhance excretion – ion trapping (alkalinize urine), forced diuresis, hemodialysis** **Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…**

Question 52

Aspirin Dose dependent effect

Answer 52

Question 53

what is Acetaminophen

Answer 53

Acetaminophen is an effective alternative to aspirin as an analgesic-antipyretic agent; however, unlike aspirin, its anti-inflammatory activity is weak and thus it is not a useful agent to treat inflammatory conditions. The failure of acetaminophen to exert anti-inflammatory activity may be attributed to the fact that acetaminophen is only a **weak inhibitor of cyclooxygenase** ( **reversible**) in the presence of the high concentrations of peroxides that are found in inflammatory lesions

Question 54

Differences between NSAIDS and Acetaminophen

Answer 54

Question 55

pharmacokinetics and metabolism of NSAIDS

Answer 55

\*not considered an NSAID anymore ## Footnote Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract. The concentration in plasma reaches a peak in 30 to 60 minutes, and the half-life in plasma is about 2 hours after therapeutic doses. Acetaminophen is relatively uniformly distributed throughout most body fluids. After therapeutic doses, 90% to 100% of the drug may be recovered in the urine within the first day, primarily after hepatic conjugation with glucuronicacid (about 60%), sulfuric acid (about 35%), or cysteine (about 3%); small amounts of hydroxylatedand deacetylated metabolites also have been detected.

Question 56

Acetaminophen at large doses produces what ?

Answer 56

ingestion of large doses of acetaminophen can produce N-acetyl-benzoquinoneimine (NABQNE)- which is a highly reactive intermediate is formed in amounts sufficient to deplete hepatic glutathione; under these circumstances, reaction with sulfhydryl groups in hepatic proteins is increased and hepatic necrosis can result, perhaps in part as a result of intracellular accumulation of Ca2+, activation of Ca2+-dependent endonuclease, and resultant DNA fragmentation (apoptosis).

Question 57

toxicity- acetaminophen

Answer 57

The most serious adverse effect of acute overdosageof acetaminophen is a dose-dependent, potentially fatal hepatic necrosis •Nausea, vomiting, anorexia, and abdominal pain occur during the initial 24 hours and may persist for a week or more•The principal antidotal treatment is the administration of sulfhydryl compounds, which probably act, in part, by replenishing hepatic stores of glutathione. N-acetylcysteine Skin rash and other allergic reactions occur occasionally

Question 58

Propionic acid derivatives

Answer 58

***ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen,*** **and** ***oxaprozin*** The pharmacodynamic properties of the propionic acid derivatives do not differ significantly. All are effective **_reversible_** cyclooxygenase inhibitors, although there is considerable variation in their potency. For example, naproxen is approximately 20 times more potent than aspirin, while ibuprofen, fenoprofen, and aspirin are roughly equipotent as cyclooxygenase inhibitors. All of these agents alter platelet function and prolong bleeding time, and it should be assumed that any patient who is intolerant of aspirin also may suffer a severe reaction after administration of one of these drugs.

Question 59

**Pharmacokinetics and Metabolism - Ibuprofen**

Answer 59

**Ibuprofen** is rapidly absorbed after oral administration, and peak concentrations in plasma are observed after 1 to 2 hours. The half-life in plasma is about 2 hours. Absorption also is efficient, although slower, from suppositories. Ibuprofen is extensively (99%) bound to plasma proteins The excretion of ibuprofen is rapid and complete. More than 90% of an ingested dose is excreted in the urine as metabolites or their conjugates. The major metabolites are a hydroxylated and a carboxylated compound.

Question 60

toxic effects - ibuprofen

Answer 60

Ibuprofen has been used in patients with a history of gastrointestinal intolerance to other NSAIDs. Gastrointestinal side effects are experienced by 5% to 15% of patients taking ibuprofen; epigastric pain, nausea, heartburn, and sensations of "fullness" in the gastrointestinal tract are the usual difficulties. Other side effects of ibuprofen have been reported less frequently. They include thrombocytopenia, skin rashes, headache, dizziness and blurred vision, and, in a few cases, toxic amblyopia, fluid retention, and edema. Patients who develop ocular disturbances should discontinue the use of ibuprofen. Ibuprofen is not recommended for use by pregnant women, or by those who are breast-feeding their infants

Question 61

**Naproxen**

Answer 61

**Pharmacokinetics and Metabolism**. Naproxen is fully absorbed when administered orally. The rapidity, but not the extent, of absorption is influenced by the presence of food in the stomach. Peak concentrations in plasma occur within 2 to 4 hours and are somewhat more rapid after the administration of naproxen sodium. Absorption may be accelerated by the concurrent administration of sodium bicarbonate or reduced by magnesium oxide or aluminum hydroxide. Naproxen also is absorbed rectally, but peak concentrations in plasma are achieved more slowly. The half-life of naproxen in plasma is about 14 hours; this value is increased about twofold in elderly subjects and may necessitate adjustment of dosage.

Question 62

Metabolism - Naproxen

Answer 62

Metabolites of naproxen are almost entirely excreted in the urine. About 30% of the drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as the glucuronide or other conjugates. Naproxen is almost completely (99%) bound to plasma proteins following normal therapeutic doses. Naproxen crosses the placenta and appears in the milk of lactating women at approximately 1% of the maternal plasma concentration.

Question 63

toxic effects naproxen

Answer 63

**Toxic Effects**. Although the incidence of gastrointestinal and CNS side effects is about equal to that caused by aspirin, naproxen is better tolerated in both regards. Gastrointestinal complications have ranged from relatively mild dyspepsia, gastric discomfort, and heartburn to nausea, vomiting, and gastric bleeding. CNS side effects range from drowsiness, headache, dizziness, and sweating to fatigue, depression, and ototoxicity. Less common reactions include pruritus and a variety of dermatological problems.

Question 64

Indomethacin

Answer 64

•Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate acute pain and relieve symptoms of arthritis (osteoarthritis and rheumatoid arthritis) or gout, such as inflammation, swelling, stiffness, and joint pain. ## Footnote **Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation.** Indomethacin has two additional modes of actions with clinical importance: •It inhibits motility of polymorphonuclear leukocytes, similar to colchicine.•It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates. These additional effects account as well for the analgesic and the anti-inflammatory properties.

Question 65

Adverse effects - indomethacin

Answer 65

•Since indomethacin inhibits both COX-1 and COX-2, it inhibits the production of prostaglandins in the stomach and intestines which maintain the mucous lining of the gastrointestinal tract.• Indometacin, like other nonselective COX inhibitors, can cause peptic ulcers. The ulcers can result in serious bleeding and/or perforation requiring hospitalization of the patient. This may have a fatal outcome stemming from these complications.•To reduce the possibility of peptic ulcers, indomethacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50–200 mg/day for the shIndometacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: ## Footnote •edema •hyperkalemia •hypernatremia •hypertension The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage) and worsens Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects. Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections. The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of _second choice_. ortest time peroid. It should always be taken with food. Indometacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: •edema •hyperkalemia •hypernatremia •hypertension The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage) and worsens Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects. Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections. The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of _second choice_. Indometacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: •edema •hyperkalemia •hypernatremia •hypertension The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage) and worsens Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects. Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections. The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of _second choice_. Indometacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: •edema •hyperkalemia •hypernatremia •hypertension The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage) and worsens Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects. Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections. The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of _second choice_.

Question 66

Other affects of indomethacin

Answer 66

Indometacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: •edema •hyperkalemia •hypernatremia •hypertension The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage) and worsens Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been reported. Skin reactions and photosensitivity are also possible side effects. Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections. The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of _second choice_.

Question 67

Nonacetylated Salicylates- Celecoxib (Celebrex)

Answer 67

Celebrex relieves the pain and inflammation of osteoarthritis and rheumatoid arthritis. It is the first of a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) called "COX-2 inhibitors." however, it does not interfere with COX-1; Celecoxib is highly selective for COX-2 (375X more than COX-1) Celebrex is therefore less likely to cause the bleeding and ulcers that sometimes accompany sustained use of the older NSAIDs. It does not affect platelet aggregation. Celebrex has also been found to reduce the number of colorectal polyps (growths in the wall of the lower intestine and rectum) in people who suffer from the condition called familial adenomatous polyposis (FAP), an inherited tendency to develop large numbers of colorectal polyps that eventually become cancerous.

Question 68

Cox 2 selective drugs

Answer 68

COX-2 can be up-regulated in the CNS and plays an essential role in the mediation of pain and the febrile response COX-2 selective inhibitors are generally larger molecules than NSAIDs and therefore preferentially inhibit COX-2 compared to COX-1 because the hydrophobic channel of COX-2 is larger. That is, COX-2 selective inhibitors are too bulky to access the binding pocket of the COX-1 enzyme

Question 69

**Incidence of endoscopic gastroduodenal ulcers with a COX-2 specific inhibitor Celecoxib**

Answer 69

Patients with rheumatoid arthritis were treated with celecoxib (100, 200, or 400 mg twice daily), naproxen 500 mg twice daily, or a placebo for 12 weeks. **Rates of gastroduodenal ulceration with naproxen were statistically higher** (\**P* \< 0.01) than rates with celecoxib or a placebo. (Data from Simon LS, Weaver AL, Graham DY, et al: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 282:1921–1928, 1999.)

Question 70

Side effects -celebrex

Answer 70

•Celebrex and other NSAID medicines can cause serious problems such as liver damage. Some of the warning signs of liver damage are nausea, vomiting, tiredness, loss of appetite, itching, yellow coloring of skin or eyes, “flu-like” symptoms and dark urine. If these happen, stop taking Celebrex and call your health care provider right away. •Celebrex and other NSAID medicines can cause serious kidney problems that include sudden kidney failure or worsening of kidney problems that you already have. •Celebrex and other NSAID medicines can cause fluid retention and swelling. Fluid retention can be a serious problem if high blood pressure or heart failure is also present

Question 71

Major health concerns of Celebrex

Answer 71

Major health concerns have been raised in regarding the use of Celebrex. An article published in August, 2001 in the medical journal *JAMA*(Journal of the American Medical Association) raised concerns over the possible impact on cardiovascular health. **Celebrex increases the risk of heart attack and stroke**

Question 72

Celebrex causes what syndrome rarely

Answer 72

Celebrex contains a sulfonamide derivative as one of its components, which are well known to cause [Stevens-Johnson syndrome.](http://www.skinassn.org/what-is-stevens-johnson-syndrome.html) The reaction usually develops within 1-4 weeks from the onset of starting drug therapy. However, the beginning symptoms can develop within hours or days and include mild rash, or mucosal lesions or fever of an unexplained origin. Mucosal lesions include lesions of the mouth, eyes, GI and respiratory tract, anus, penis and vagina.

Question 73

NSAID usage

Answer 73

*A panel of experts developed an algorithm to guide the use of NSAIDs in patients with different gastrointestinal and cardiovascular risks.* Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed but carry both gastrointestinal and cardiovascular (CV) risks. Multiple guidelines offer recommendations for mitigating the GI risks associated with NSAIDs (e.g., bleeding), but strategies for simultaneously dealing with the GI and CV risks of these drugs have not been published. To bridge this gap, the Canadian Association of Gastroenterology convened a panel of 21 physician-experts to develop evidence-based recommendations for long-term (\>4 weeks) NSAID use.

Question 74

Patients with low GI and low CV risks should receive a

Answer 74

traditional NSAID.

Question 75

Patients with low GI and high CV risks should receive

Answer 75

naproxen.

Question 76

Patients with high GI and low CV risks should receive

Answer 76

a cyclooxygenase-2 inhibitor plus a proton-pump inhibitor

Question 77

Patients with high GI and high CV risks should receive a

Answer 77

careful assessment to prioritize risks.

Question 78

NSAIDs should be prescribed

Answer 78

at the _lowest_ effective dose and for the **_shortest_**possible duration.

Question 79

**Contraindications and drug interactions**

Answer 79

vChildren and teenagers with viral infections - vReyes Syndrome. vAspirin should not be used in patients with abnormal bleeding / anticoagulant therapy. Increased risk of hepatotoxicity when given with alcohol, barbiturates, anticonvulsants, rifampin

Question 80

Drug Interaction

Answer 80

NSAIDs are highly bound to albumen and will displace other drugs from these binding sites causing increased concentration of active drugs in the blood such as * Oral anticoagulants, e.g., warfarin * Antibiotics, Anticonvulsants, Methotrexate * •Some antihypertensive drugs (β-blockers, ACE inhibitors and diuretics) are antagonized.

Question 81

**A suggested treatment algorithm**

Answer 81

Question 82

Examples of Corticosteroids available

Answer 82

´hydrocortisone ´prednisolone´dexamethasone´beclomethasone ´budesonide´fluticasone

Question 83

uses of corticosteroid drugs

Answer 83

´Corticosteroids are used:· to reduce inflammation (asthma, arthritis) and swelling (cerebral edema) ·to suppress the immune response (systemic lupus erythematosus) ·to reduce nausea and vomiting (as in cancer chemotherapy) ·to reduce terminal pain (associated with cancer) ·as replacement therapy (in Addison’s disease)

Question 84

Where to corticosteroids work in the inflammatory cascade

Answer 84

Question 85

* *Mechanism of Action for** * *Anti-Inflammatory Steroids**

Answer 85

1. **Suppress T-cell activation and cytokine production.**● 2. **Suppress mast cell degranulation.**● 3. **Decrease capillary permeability indirectly by inhibiting mast cells and basophils.**● 4. **Reduce the expression of cyclooxygenase II and prostaglandin synthesis.**● 5. **Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A2 activity.**

Question 86

**Mechanism of action** – Glucocorticoids

Answer 86

´Glucocorticoids suppress the cell-mediated immunity. They primarily act by inhibiting genes that code for the cytokines Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, _the most important of which is IL-2_. ´Glucocorticoids influence all types of inflammatory events. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production.´The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.

Question 87

**Routes of Administration for GC**

Answer 87

´_Local_ (Preferred)´Intra-articular, IA´Intrabursal, IB´Intralesional, IL´Intrasynovial, IS´Soft tissue, ST´Intrarectal, IR´Topical´Nasal´Inhaled ´´_Systemic_´Oral, PO´Intramuscular, IM´Intravenous, IV´Subcutaneous, SC

Question 88

**Pharmacokinetics of GC**

Answer 88

´Daily administration of corticosteroids at physiological concentrations for at least 2 weeks suppresses the HPA resulting in decreased production of endogenous hormones. Recovery may take up to 9-12 months. ´´_Hepatic Metabolism_:´The liver is the primary site of GC inactivation. GCs are metabolized by cytochrome P450 3A4 enzymes´25% of GCs are excreted in bile and feces.´ ´_Renal Clearance_´75 % of GC metabolites are excreted in the urine.

Question 89

**Glucocorticoids Regulate Transcription: How?**

Answer 89

**GR, glucocorticoid receptor; HSP, heat shock protein; IP, immunophilin;GRE, glucocorticoid receptor**

Question 90

**Corticosteroids Inhibit Eicosanoid Production: How?**

Answer 90

Question 91

* *Glucocorticoids Are Powerful** * *Immuno-suppressants**

Answer 91

***Corticosteroids affect nearly every facet of immune function,*** ***although less inhibition of humoral arm than cell-mediated arm;*** ***they also induce apoptosis in rapidly-dividing leukocytes***

Question 92

**Adrenal Suppression with Chronic Systemic Glucocorticoids**

Answer 92

some people gain weight

Question 93

compare corticosteroids

Answer 93

Question 94

what are short acting, medium acting and long acting drugs of corticosteroids

Answer 94

**Corticosteroids control symptoms and DO NOT stop progression (cure) of the disease**

Question 95

Prednisone

Answer 95

´Intermediate acting GC ´´Clinical uses: Adjunct therapy for arthritis (short term admin), asthma, COPD; Ulcerative colitis and Crohn’sdisease.; Rheumatic and dermatologic disorders. ´Relative anti-inflammatory potency is 4; It is 4x more potent than cortisol.´ ´Inactive on its own. It must be metabolized in the liver to an active metabolite. ´Plasma half-life is 60 min ´Biological half-life is 18-36 hrs´Administration: Oral only.

Question 96

prednisolone

Answer 96

´Intermediate acting GC ´´Prenisolone acetate/sodium phosphate ´´Clinical uses: Opthalmic disorders, respiratory diseases. ´´Plasma half-life is 60 min´´Biological half-life is 18-36 hrs .´´Administration: Oral, Injectable (systemic and local).

Question 97

**Methylprednisolone**

Answer 97

´Intermediate acting GC ´´Methylprenisolone acetate/sodium succinate ´´Clinical uses: Rheumatoid arthritis Intra-articular injections´, UC, severe alcoholic hepatitis. ´´Plasma half-life is 60 min´´Biological half-life is 18-36 hrs .´´Administration: Oral, Injectable (systemic and local).´ ´Adverse effects: vertigo, headache, weight gain, sodium/water retention and impaired wound healing.

Question 98

**Triamcinolone**

Answer 98

´Intermediate acting GC ´´Triamcinolone acetonide/diacetate/hexacetonide´ ´Clinical uses: Similar to prednisone: Opthalmicdisorders, respiratory diseases. ´´Plasma half-life is 60 min ´´Biological half-life is 18-36 hrs.´Administration: Oral, Injectable (systemic and local).

Question 99

* *Inhaled Glucocorticoids:** * *“Long-term control” of Chronic Asthmatic Symptoms**

Answer 99

Beclomethasone Budesonide Flunisolide Fluticasone propionate Triamcinolone acetonide _Mechanisms of Action_: ´Reduce bronchial hyperreactivity´Decreased synthesis and release of inflammatory mediators, e.g, leukotrienes, prostaglandins and histamine ´Decreased infiltration and activity of inflammatory cells, e.g. eosinophils, leukocytes) ´Decreased edema of the airway mucosa and mucus production´Increase responsiveness to b₂ agonists

Question 100

´Anti-inflammatory Drugs

Answer 100

´*Glucocorticoids*´Inhaled´Beclomethasone´Budesonide´Flunisolide´Fluticasone propionate´Triamcinolone acetonide´´´´Oral (Quick relief of asthmatic symptoms)´Prednisone´Prednisolone´*\* Unresponsive to b2 agonists*

Question 101

Unwanted Effects- corticosteroids

Answer 101

´**Metabolic:**´growth suppression´diabetes mellitus´muscle wasting´osteoporosis´fat redistribution´skin atrophy´hirsutismacne ## Footnote ´hypertension´hypokalaemia´menstrual irregularities´adrenal suppression ´**Other:**´infection´emotional disturbances (psychosis, depression, mania)´cataract, glaucoma´GI bleeding, perforation´**Withdrawal**´Addisonian crisis´raised intracranial pressure´arthralgia/myalgia´pustular rash

Question 102

**Toxicity of Chronic Systemic Glucocorticoids**

Answer 102

* Fat redistribution * Hypertension * Glucose intolerance * Impaired wound healing * Osteoporosis (prevent with bisphosphonates) * Cataracts * Gastric ulcers (prevent with omeprazole, misoprostol) * Risk of infection * CNS effects, including psychosis * Growth inhibition in children

Question 103

Clinical Concerns with Corticosteroids

Answer 103

´**Growth inhibition** **in pediatric transplants**´**Cataracts** **(10% incidence)**´**Bone disease** **(inhibition of osteoblastic activity, decreased calcium absorption, increased urinary calcium excretion)**´**Diabetes** **(insulin-resistance, gluconeogenesis)**´**Hyperlipidemia** **(40-60% posttransplant accelerated atherogenesis, increased incidence if combined with calcineurin inhibitors and sirolimus)**´**Hypertension** **(60-80% in transplant patients)**´**Increased cardiovascular risk factors**´**Predisposition to infection (decr. PMN, T cell activity)**