PHARMACOLOGY OF INFLAMMATION

David J. Mokler, Ph.D.October 29, 2009

OBJECTIVES

After studying this material the student should;

Describe the role of prostaglandins in the inflammatory response.

Describe the mechanism of action of non‑steroidal drugs used in the treatment of inflammation.

Describe the pharmacology and toxicology of the non‑steroidal anti‑inflammatory agents.

Discuss the toxicity of acetaminophen

OBJECTIVES

After studying this material the student should;

Discuss the proper and rational use of corticosteroids in the treatment of inflammation.

Discuss the toxic effects of the corticosteroids used in chronic therapy.

NSAIDs – COX INHIBITORS

AspirinIndomethacin (INDOCIN) Proprionic Acid Derivatives Ibuprofen (MOTRIN, RUFEN, ADVIL, NUPRIN) Naproxen (NAPROSYN) Piroxicam (FELDENE) Nabumetone (RELAFEN)

Ketorolac (TORADOL)Acetominophen (TYLENOL, TEMPRA, others)

NSAIDs – COX INHIBITORS

COX2 Inhibitors

Celecoxib (CELEBREX)

PROSTAGLANDINS

History 1930 ‑ Kurzrok and Lieb 1930s ‑ Goldblatt, Euler "prostaglandin"‑

lipid‑ soluble acid 1962 ‑ isolation of PGE1 and PGF1 1964 ‑ synthesis from arachadonic acid

Arachadonic acid metabolites via cyclo-oxygenase Released by mechanical, thermal, chemical, bacterial and other trauma

PROSTAGLANDINS

PROSTAGLANDINS

Effects produce blood flow in injured region,

vascular permeability, enhance lymphocytic infiltration

may modulate release of histamine from mast cells ‑ PGD2 stimulates, PGE2 and PGI2 inhibits

oxygen radicals produced as byproduct of synthesis ® inflammation

potentiate pain‑producing effects of kinins produce fever in hypothalamus PGE1 and PGE2 stimulate osteoclasts ®

bone resorbtion

Fever

PROSTAGLANDINS

Effects PGE1 and PGD2 inhibit platelet

aggregation TXA2 induces aggregation PGA2, PGE1 and PGE2 induce

erythroporesis PGFs contract, PGEs relax bronchial

smooth muscle, non‑pregnant and pregnant uterus

DuBois RN, et al. FASEB J. 1998;12:1063–1073.DuBois RN, et al. FASEB J. 1998;12:1063–1073.

COX-1

· Produces prostanoids that mediate homeostaticfunctions

· Constitutively expressed· Especially important in:

– Gastric mucosa; small- and large-bowel mucosa

– Kidney– Platelets– Vascular endothelium

COX-1

· Produces prostanoids that mediate homeostaticfunctions

· Constitutively expressed· Especially important in:

– Gastric mucosa; small- and large-bowel mucosa

– Kidney– Platelets– Vascular endothelium

COX-2

· Produces prostanoids that mediate inflammation, pain, and fever

· Induced mainly at sites of inflammation by cytokines

· Constitutive expression in:– Brain– Kidney (mainly animal data)– Female reproductive tract

COX-2

· Produces prostanoids that mediate inflammation, pain, and fever

· Induced mainly at sites of inflammation by cytokines

· Constitutive expression in:– Brain– Kidney (mainly animal data)– Female reproductive tract

Two Forms ofCyclo-oxygenase (COX)

Mediate inflammation,pain, and fever

Mediate inflammation,pain, and fever

Arachidonic acidArachidonic acid

COX-2–targeted agents

COX-2–targeted agents

Protect gastroduodenal

mucosa

Protect gastroduodenal

mucosa

XX

ProstaglandinsProstaglandinsProstaglandinsProstaglandins ThromboxaneThromboxane

Supportsplateletfunction

Supportsplateletfunction

COX-1COX-1 COX-2COX-2

Traditional NSAIDs

Traditional NSAIDs

XXXX

Mechanism of Action of Anti-inflammatory Agents

LEUKOTRIENES

arachidonic acid metabolites from lipoxygenase

may be inhibited by some NSAIDs, inhibited by steroids

LEUKOTRIENES

LEUKOTRIENES

Effects LTB4 potent chemotaxic substance act on endothelium of postcapillary venules

to cause exudation of plasma 5‑HPETE and 5‑HETE induce release of

histamine from basophils LTC4 and LTD4 potent bronchoconstrictors

LTD4 is the slow reacting substance of anaphylaxis (SRSA) ® bronchoconstriction, histamine release, vasopermeability

OTHER MEDIATORS OF INFLAMMATION

Histamine5‑hydroxytryptamine (Serotonin)Bradykinins Vasopermeability histamine release prostaglandin synthesis Pain

NSAIDsSALICYLATES

Aspirin – acetylsalicylic acid (ASA)

NSAIDsASPIRIN (ASA)

Mechanism of action inhibits prostaglandin synthesis by

acetylation of cyclooxygenase

Pharmacological actions Analgesia Anti-inflammatory Antipyretic action

NSAIDsSALICYLATES

Pharmacokinetics rapid absorption- low pH increases absorption-

high pH increases solubility, enhances absorption peak blood levels: 2 hours up to 90% protein bound in plasma metabolism in liver‑glycine or glucuronide

conjugates; 10% is free salicylate excretion in urine free salicylate excretion (not metabolites) may

be enhanced by making the urine more alkaline

NSAIDsSALICYLATES

Toxicity large doses will increase depth of

respiration nausea and vomiting salicylism ‑ chronic treatment of high

doses- confusion-delerium- tinnitus – dizziness

increased bleeding time gastric ulceration (especially with alcohol) hemorrhage

may alter uric acid excretion (dose dependent)

Toxicity

Overdose acid‑base changes ‑ usually acidosis,

metabolic & respiratory High doses suppress respiration →

respiratory acidosis Uncouple oxidative phosphorylation in

cells → metabolic acidosis

PROPRIONIC ACID DERIVATIVES

Ibuprofen (MOTRIN, ADVIL, NUPRIN) rapidly absorbed after oral administration,

peak concentration 1 to 2 hours extensively (99%) protein bound, 90%

excreted as metabolites in urine 

Naproxen (NAPROSYN) longer half life, therefore 2 x day dosing inhibits PMN migration

Piroxicam (FELDENE)Nabumetone (RELAFEN)

PROPRIONIC ACID DERIVATIVES

anti‑inflammatory, anti‑pyretic, analgesicinhibit cyclooxygenase, inhibit leukocyte migration possibly by inhibition of lipoxygenaseBetter anti-inflammatory than aspirin?

PROPRIONIC ACID DERIVATIVES

Toxicity – this relates to all NSAIDs Increased bleeding time Gastric bleeds Long term may cause liver toxicity Hypertension and renal failure

especially in the elderly Edema CNS – dizziness, confusion, drowsiness,

anxiety

Ketorolac (TORADOL)

High potency, analgesia equivalent to morphineUsed for moderate to severe painNot for mild painShort term peri-operative useSimilar side effects to other NSAIDs

Indomethecin (INDOCIN)

Potent inhibitor of cyclooxygenase, inhibits PMN migration Analgesic, anti‑inflammatory and anti‑pyretic ‑ similar to aspirinRapidly and completely absorbed following oral administration, 90% protein bound, low concentrations in CSF but plasma levels in synovial fluidToxicity ‑ 35 to 50% of patients receiving therapeutic doses report side effects: GI ‑ anorexia, nausea, abdominal pain, ulceration of upper GI tract: CNS ‑ severe frontal headache most common (25‑50%), dizziness, vertigo, light‑headedness, mental confusion: hematopoietic reactions, hypersensitivity (cross-sensitivity with aspirin)

Mean Plasma half-lives of different NSAIDS

Drug Half-life (hr)

ShortAspirin

0.25Diclofenac 1.1

Etolodac 3.0Ibuprofen 2.1Indomethacin 4.6

Ketoprofen 1.8 

LongDiflunisal 15Naproxen 14Phenylbutazone 68Piroxicam 57

Sulindac 14   

Acetaminophen (TYLENOL)

 Actions Analgesic, antipyretic properties comparable to

salicylates Weak inhibitor of prostaglandin biosynthesis in

periphery, more activity in CNS Identification in 2002 of COX-3 in brain that has

a higher affinity for acetaminophen – now thought to be a splice variant of COX-1

Weak anti-inflammatory action No effect on respiration No effect on platelets No effect on uric acid excretion

Acetaminophen (TYLENOL)

Pharmokinetics rapid absorption peak blood levels: 1‑2 hours acetaminophen to glucuronide conjugation excreted in urine

Acetaminophen (TYLENOL)

Toxicity Allergic reactions (rare) Toxicity at therapeutic doses

2 extra strengths = 1000 mg FDA panel recommends no more than 650 mg per

dose Recommends total daily dose less than 4000 mg Evidence of long term hepatic toxicity with long

term use Use of acetaminophen in many combination

products

Acetaminophen (TYLENOL)

Toxicity in overdose No acute signs but

medical emergency

Hepatic necrosis, renal tubular necrosis emerges over days

Hypoglycemic coma

Treatment acetylcysteine

COX2 inhibitor

Celecoxib (CELBREX)Selectively inhibit COX2 – inducible cyclo-oxygenaseMay be no better than non-selective inhibitors

Gastrointestinal Toxicity With Celecoxib vs

Nonsteroidal Anti-inflammatory Drugs

for Osteoarthritis and Rheumatoid Arthritis

The CLASS Study: A Randomized Controlled Trial

JAMA 284(10): 1247, 2000

http://jama.ama-assn.org/issues/v284n10/rfull/joc01227.html

Figure 2. Annualized Incidence of Upper Gastrointestinal Tract Ulcer Complications Alone and With Symptomatic Gastroduodenal Ulcers

Figure 3. Patients With Decreases inHematocrit and/or Hemoglobin at 6 Months

Figure 4. Patients With Increases in Serum Creatinine and/or Serum Urea Nitrogen and With Elevations in ALT and AST at 6 Months

What happened to the COX-2 inhibitors??

Rofecoxib (VIOXX) withdrawn

In APPROVe trialDesigned to evaluate the efficacy of rofecoxib, 25 mg, in preventing recurrence of colorectal polyps in 2,600 patients with a history of colorectal adenomasThe increased cardiovascular risk began after 18 months of treatment with rofecoxib and persisted. At three years, cumulative incidence of cardiovascular events was 7.5 per 1,000 patients receiving placebo compared with 15 per 1,000 patients receiving rofecoxib

Mechanisms of cardiovascular toxicity

COX-1 helps promote thrombosis and COX-2 helps inhibit it, blocking COX-2 but not COX-1 could theoretically increase the risk of myocardial infarction and other thrombotic events.

Mechanisms of cardiovascular toxicity (con’t)

Depression of prostaglandin I2 formation by coxibs might be expected to elevate blood pressure, accelerate atherogenesis, and increase the thrombotic response to rupture of an atherosclerotic plaque. In patients at higher cardiovascular risk, coxibs would be more likely to predispose to a clinical event early in the course of treatment

CONSIDERATIONS OF THERAPY WITH NSAIDs

Most NSAIDs are similar in efficacy Patient variability in efficacy and toxicity

Classification by duration of actionSide effects serve as the basis for therapeutic choiceInhibition of cyclooxygenase varies as to distribution in body fluidsAspirin and para‑aminophenol toxicityBlood dyscrasias

TREATMENT OF ARTHRITIS WITH NSAIDs

Reduced inflammation slows progress of diseaseHigh dose therapyAged population monitor renal function monitor blood for dyscrasias

Use best tolerated agent and lowest cost

ANTI-INFLAMMATORY STEROIDS

David J. Mokler, Ph.D.

October 29, 2009

CORTISOL

Chemistry & Metabolism major glucocorticoid in humans synthesized from cholesterol in cells of the zona

fasiculata and zona reticularis of the adrenal cortex

released under the influence of ACTH 20 mg secreted per day in adult in the absence

of stress 95% bound in blood to corticosteroid binding

globulin T½ 90‑110 min; increased with large amounts or

hypothyroidism reduced and conjugated in liver, excreted in

urine as 11‑oxy 17‑ketosteroids

Physiologic and Pharmacological Effects

Widespread effects ‑ homeostasisDose‑related and "permissive" effects

Effects on metabolism Protects glucose-dependent tissue (brain

and heart) In periphery decreases glucose utilization Increases blood glucose Stimulates gluconeogenesis glycogen stores Anti‑insulin effects

Physiologic and Pharmacological Effects

Cardiovascular decrease capillary permeability, incr in Na+

retention

Blood elements ↑ hemoglobin and red blood cells, ↑ PMN

leukocytes ↓ lymphocytes, eosinophils, monocytes,

basophils ↓ lymphoid tissue and immune response

Mechanisms of Action

Glucocorticoid Receptor Signaling SIGMA-ALDRICH

STEROIDS FOR THOUGHT

Anti-Inflammatory Properties

Inhibit early phase (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytic activity)Inhibit late phase (capillary proliferation, fibroblast proliferation, deposition of collagen and cicatrization)Inhibit inflammatory response regardless of inciting agent ‑ palliative therapyInhibit recruitment of neutrophils and monocyte ‑ macrophages

SYNTHETIC CORTICOSTEROIDS

 Structure for ↑ glucocorticoid activity 1, 2 double bond ‑ prednisone, prednisolone ‑

enhances glucocorticoid effects 6α ‑methylation ‑ unpredictable ‑ 6α‑

methyl‑prednisolone ‑ increased anti‑inflammatory 9‑fluoridation ‑ increases all activity ‑

paramethasone, betamethasone, dexamethasone 16‑methylation eliminates Na+ retaining effect with

slight change in metabolic and anti‑inflammatory effect

17 α‑hydroxy ‑ maximizes carbohydrate and anti‑inflammatory potency

SAR and parallel activity of glucose metabolic and anti‑inflammatory activity suggests similar receptor mechanisms

Relative Potencies

Anti-inflammatoryNa+

Cortisol 1 1Prednisone 4 0.8(Δ1-Cortisone)Prednisolone 4 0.8Fludrocortisone 10 125Corticosterone 0.35 15Triamcinalone 5 0(9α-Fluoro-16α-hydroprednisolone)Paramethasone 10 0(6α-Fluoro-16α-methylprednisolone)Betamethasone 25 0(9α-Fluoro-16β-methylprednisolone)Dexamethasone 25 0(9α-Fluoro-16α-methylprednisolone)

PHARMACOKINETICS

Well absorbed after oral administrationAlso available for i.v, i.m., intrasynovial and topical administration90% protein bound to corticosteroid‑binding globulin ‑ increases during pregnancy and administration of estrogens and cortisol Hepatic and extra-hepatic metabolism

TOXICITY OF STEROIDS

Acute and Subacute

days or a few weeks few adverse effects behavioral changes acute peptic ulcers

TOXICITY OF STEROIDS

Chronic Therapy – Withdrawal acute adrenal insufficiency withdrawal syndrome ‑ fever, myalgia,

arthralgia, malaise

Chronic Therapy - Continued High Dose Therapy Adrenal suppression

supplementary therapy at times of severe stress  accidental trauma, surgery recovery following withdrawal, may take 6‑9

months following chronic treatment

TOXICITY OF STEROIDS

Chronic Therapy - High Dose Therapy Iatrogenic Cushing's syndrome

redistribution of body fat from extremities to trunk and face

striae, ecchymoses, acne and hirsutism Increased susceptibility to infection

Nonspecific aggressive treatment with drugs specific for

pathogen Hypokalemia, hypochloremia, edema ‑ not seen with

16‑substituted compounds Behavioral disturbances, psychoses ‑ nervousness,

insomnia, changes in mood, manic‑depressive or schizophrenic symptoms, suicidal tendencies

TOXICITY OF STEROIDS

Chronic Therapy - High Dose Therapy Cataracts Osteoporosis

in all ages inhibition of osteoblasts and Ca++ uptake,

secretion PTH (+) osteoclasts, therefore formation and resorbtion

indication for withdrawal from therapy

Growth retardation in children ‑ not reversible by exogenous HGH

THERAPEUTIC USES

 Substitution therapy acute - cortisol in dose equivalent to

maximum daily rate of secretion in stress - with intravenous isotonic saline

chronic - cortisol in twice daily dosing to mimic diurnal cycle - with mineralocorticoid

Arthritis rheumatoid

lowest dose to alleviate symptoms continue NSAIDs, rest, physical therapy

osteoarthritis - intra-articular injection - controversial

THERAPEUTIC USES

Rheumatic carditis ‑ non-responsive to salicylates -in combination with salicylatesRenal diseases ‑ in some cases of acute and chronic glomerulonephritis with nephrotic syndromeCollagen diseases ‑ most diseases associated with collagen except scleroderma - life threatening, fulminating SLEAllergic disorders - manifestations of short duration controlled - used in combination with other agents - not effective for severe acute reactions - Why? 

THERAPEUTIC USES

Ocular diseases - contraindicated in herpes simplex, mechanical lacerations, or fungal, viral or bacterial infectionsSkin diseases - topical steroids - psoriasis, vitiligo, seborrheaLiver diseases - only certain patients with chronic active hepatitisCerebral edema ‑ neoplasia, no strong evidence for value in edema due to trauma, cerebro-vascular accident or shock

THERAPEUTIC CONSIDERATIONS

 Empirical use ‑ 6 principles Careful titration of dose A single dose of steroid, even large, has

very little harmful effect A few days of therapy at moderate doses

and in the absence of contraindications is unlikely to produce harmful effects

Increased toxicity with increased dose and increased duration of therapy

Not curative except for adrenal insufficiency Abrupt withdrawal following high‑dose

therapy may be life‑threatening