pharmacology of inflammation
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PHARMACOLOGY OF INFLAMMATION
David J. Mokler, Ph.D.October 29, 2009
OBJECTIVESAfter 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
OBJECTIVESAfter 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)
PROSTAGLANDINSHistory 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
PROSTAGLANDINSEffects 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
PROSTAGLANDINSEffects 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.
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
Two Forms ofCyclo-oxygenase (COX)
Mediate inflammation,
pain, and fever
Arachidonic acidCOX-2–targeted
agents
Protect gastroduodenal
mucosa
X
ProstaglandinsProstaglandins Thromboxane
Supportsplateletfunction
COX-1 COX-2Traditional
NSAIDsXX
Mechanism of Action of Anti-inflammatory Agents
LEUKOTRIENES
arachidonic acid metabolites from lipoxygenase
may be inhibited by some NSAIDs, inhibited by steroids
LEUKOTRIENES
LEUKOTRIENESEffects 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 cyclooxygenasePharmacological 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 migrationPiroxicam (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 inhibitorCelecoxib (CELBREX)Selectively inhibit COX2 – inducible cyclo-oxygenaseMay be no better than non-selective inhibitors
Gastrointestinal Toxicity With Celecoxib vsNonsteroidal Anti-inflammatory Drugs
for Osteoarthritis and Rheumatoid ArthritisThe CLASS Study: A Randomized Controlled
TrialJAMA 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
CORTISOLChemistry & 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+
retentionBlood 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 PotenciesAnti-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)
PHARMACOKINETICSWell 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 STEROIDSChronic Therapy – Withdrawal acute adrenal insufficiency withdrawal syndrome ‑ fever, myalgia,
arthralgia, malaiseChronic 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 STEROIDSChronic 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 STEROIDSChronic 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 USESRheumatic 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
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