Mediators of Inflammation

and Anti-inflammatory

Drugs

Done by: Dr. Noor Najjar

InflammationMediators of inflammationNSAIDsOpoids Combination Analgesia

Outline

CAUSE OF INFLAMMATION

Inflammation typically represents the response to tissue injury and includes products of activated mast calls, leukocytes, and platelets.

The clinical features of inflammation include1. tumor (edema)2. rubor (redness)3. Calor (heat)4. dolor (pain)5. loss of function.

Inflammation can be divided into three phases:a) Acute inflammation Inflammatory mediators such as histamine are

released.

b) Subacute inflammationInflammatory cells migrate and invade the site. PGs, leukotrienes, platelet-activating factor

(PAF), and cytokines are prominent in this stage.

c) chronic inflammation.lymphocytic phase of injury cleansing and repair. Cytokines, especially interleukins and tumor

necrosis factor-α (TNF-α), are prominent in this stage .

In reality these phases are not distinct entities. Components of the subacute phase participate in the acute inflammatory process, and acute inflammatory mediators are present in chronic inflammatory disorders.

1HistamineProstaglandinsLeukotrinesLysosomal productsLymphocyte productsMacrophage productsMast cell productsEosinophile products Plasma protein derived Mediators Nitric Oxide

Tissue mediators

Tissue Mediators1. HistamineHistamine is the first mediator which has a

role in the inflammatory process.Most of the histamine is stored in mast cells

and basophilic granules, only some of it exists as free active in tissues.

Various physical and chemical stimuli -antigens, complement fragments, or simple mechanical trauma- causes extrusion of the granules and release of active histamine into the extracellular fluid.

Histamine causes:I. dilation of vessels of the microcirculation II. Marked but transient, increase in the

permeability of capillaries and post-capillary venules.

The histamine content of tissue fluid at the site of injury increases within minutes after the insult and then decreases gradually.

Antihistamines have little use as general anti-inflammatory agents. However, antihistamines that block the H1 receptor are useful in reducing symptoms attributable to histamine in allergic reactions.

2. ProstaglandinsPGs are derived from arachidonic acid. Also can be

generated by inflammatory cells.PGs exert a multitude of effects in almost every

biologic process :A. smooth muscle contraction and relaxationB. vascular permeabilityC. renal electrolyte and water transportD. gastrointestinal (GI) and pancreatic secretionE. various CNS and autonomic nervous system

functionsF. release of hormonesG. Bone resorptionH. Platelet aggregation

PGs are being formed and released at times when tissue damage and disintegration are more prominent especially during phagocytosis.

PGI2 and PGE2 are potent inducers of vasodilation and of increased vascular permeability, which may last for several hours.

PGE2 is pyrogenic, suggesting a mediator function.

Certain anti-inflammatory drugs that are potent inhibitors of PG synthesis reduce experimentally produced inflammation.

All cells except erythrocytes can convert arachidonic acid to PGs and related compounds by the action of COX.

A balance between enhancement and suppression of inflammatory events could be achieved by local regulation of PG metabolism because in some systems PGs have been shown to be either stimulatory or inhibitory depending on their concentration.

COX-1: constitutive enzyme: is involved in tissue

homeostasis.

COX-2: inducible enzyme: is responsible for the

production of the prostanoid mediators of inflammation

COX

COX Enzyme:Prostaglandin Effects

COX-1: beneficial COX-2: harmful

Peripheral injury site

Inflammation

Brain Modulate pain perceptionPromote fever (hypothalamus)

Stomach protect mucosa

Platelets aggregation

Kidney vasodilation

3.LeukotrienesThe ability of cells to produce leukotrienes seems to be limited

tothe lung, leukocytes, blood vessels, and epicardium.Leukotrienes C4 and D4 are constrictors of bronchial smooth

muscle More potent than histamine-they increase vascular

permeability Leukotriene B4 can enhance chemotactic and chemokinetic

responses in human neutrophils, monocytes, and eosinophilsThey are involved in localized inflammatory processes and in

asthma.Drugs that block leukotriene receptors or inhibit leukotriene

synthesis by blocking the enzyme lipoxygenase are used in the treatment of asthma.

4.Lysosomal productsDuring phagocytosis of bacteria or foreign material by

neutrophils, the contents of lysosomes are released into the extracellular environment.

Cationic proteins released contribute to the inflammatory process by triggering mast cell degranulation increased vascular permeability

Several of these enzymes have the potential to damage host tissues.

Collagen, elastin, mucopolysaccharides, basement membrane, and other structural elements may be degraded.

Lysosomal proteases cause the production of kinin-like substance and can generate chemotactic factors for neutrophils from complement

5.Lymphocyte products

Delayed allergic reactions may be involved in some inflammatory processes, especially chronic processes in which there is a persistent antigenic stimulus. These reactions are mediated by factors called cytokines (lymphokines if derived from lymphocytes), which are produced by sensitized thymus-dependent lymphocytes, or T cells, after specific antigenic challenge.

Cytokines that may function in inflammation related events are:

(1) Interleukins that stimulate the function of T&B cells. (2) Monocyte chemoattractive protein-1, which

promotes accumulation of monocytes. (3) Granulocyte/macrophage colony stimulating

factor. (4) Other chemotactic factors that are specific attractants

for neutrophils, macrophages, basophils and eosinophils. (5) Interferon-á, which has antiviral and macrophage

activation properties.(6) Skin reactive factor, which mimics a delayed allergic

reaction when injected into normal skin.

6.Macrophage productsThey have Little involvement in acute

inflammatory responses, but they play a very prominent role in chronic inflammation and are crucial in the immune response.

Secretory products includea) The constituents of lysosomes b) Reactive metabolites of oxygenc) Interferon-á, interleukin-1 (IL-1), and TNF-á.

IL-1 is produced by macrophages exposed to bacterial, viral, and fungal products; antigens; or macrophage activation factor.

Main role is stimulation of differentiation of a pre–T lymphocyte population to T cells capable of responding to an antigen processed and presented by macrophages.

PAF is a mediator of inflammation produced by macrophages, mast cells and eosinophils and Platelets.

PAF initiates various actions:A. Platelet activationB. VasodilationC. Vascular permeabilityD. Neutrophil chemotaxis E. Discharge of lysosomal enzymes. F. Contributes to allergic and inflammatory responses.

7.Mast cell productsMast cells release numerous inflammatory

mediators 1. histamine2. cytokines (e.g., TNF-á)3. leukotrienes4. PGD25. PAF. Mast cells can become activated by IgE

antibodies that bind to the plasma membrane and sensitize the mast cell to specific allergens. Several allergic reactions, including allergic asthma, involve this mechanism.

Basophiles have many of the same characteristics as mast cells.

8.Eosinophil productsEosinophils release many enzymes and toxins that can lead to tissue destruction.

Major basic protein is a toxic substance that can cause tissue damage and destruction of parasites.

Eosinophils also release leukotrienes and PAF.

9.Plasma MediatorsKininsThe term kinins refers primarily to two small

peptides that are similar in structure and actions: bradykinin and lysylbradykinin

As with the release of histamine, almost any process causing tissue injury can trigger the series of events leading to the production of bradykinin.

Bradykinin exists in plasma as an inactive precursor (kininogen) and is released in a cascade of reactions.

After release, bradykinin is rapidly metabolized by enzymes present in plasma and tissues.

Bradykinin is a potent but transient vasodilator of arteries and veins by a direct action on smooth muscle.

10.Nitric Oxide (NO)

NO plays a regulatory and a pro-inflammatory role in various inflammatory conditions, including arthritis, asthma, and inflammatory bowel disease.

Currently approved drugs that target the nitric oxide system, such as nitroglycerin to treat angina and the male erectile dysfunction drug sildenafil (Viagra) increase NO levels.

Analgesics should be used judiciously in dental care as a temporary measure until the cause of pain has been dealt with.

The choice of an analgesic should be based on its suitability for the patient.

Most dental pain is relieved effectively by NSAIDs.

Analgesics are classified as 1. Non-opioid analgesics2. Opioid analgesics3. NSAIDs4. Neuropathic pain agents5. Antimigraine drugs

Analgesics

Non selective COX inhibitors:Salicylates: AspirinPropionic acid derivatives : Ibuprofen, ketoprofen, flurbiprofenFenamate: Mephanamic AcidEnolic acid derivatives: piroxicam, TenoxicamAcetic acid derivative: Ketorolac, IndomethacinPyrazolone derivatives: Phenylbutazone, OxyphenbutazonePerferential COX-2 inhibitors:Nimesulide, Diclofenac, Aceclofenac, Meloxicam, EtodolacSelective COX-2 inhibitors:Celecoxib, etoricoxib , ParecoxibAnalgesic-Antipyretic with poor antiinflammatory action:Paraaminophenol derivatives : paracetamol Pyrazolone Derivatives: propiphenazoneBenzoxazocin derivatives : Nefopam

Classification of NASIDS

For Acute Pain (e.g dental procedures) short term use ≤1 week highly efficacious and safe.

For chronic inflammatory conditions months or years with doubling the dose often 2-3folds.

NSAIDs lack various undesirable CNS depressant effects that contribute to the high incidence of drowsiness, dizziness, and nausea commonly seen with opioid-containing agents.

The development of NSAIDs that are highly selective COX-2 inhibitors seemed to offer a safety advantage regarding some of the more serious adverse effects seen with long term NSAID therapy, specifically GI ulcers, perforations, and bleeds.

Major Actions: ANALGESIA , ANTIPYRETIC , ANTI-INFLAMMATORY Except acetaminophen

Non steroidal anti-inflammatory

NSAIDs : anti-platelet—decreases ability of blood to clot

Effects of COX Inhibition by Most NSAIDS

It was first extracted in 1835 from natural sources and later prepared by chemical synthesis.

Aspirin was synthesized from salicylates (acetylsalicylic acid) by treating sodium salicylate with acetyl chloride.

It is one of the most consumed drugs in the world.

Salicylates

Mechanism of action

The efficacy of salicylates and all related NSAIDs as analgesic, anti-inflammatory, and antipyretic agents results from:

Their ability to inhibit COX activity, preventing the synthesis and release of COX products, most prominently the PGs

Note : All salicylates and almost all the currently available NSAIDs, with the exception of the highly selective COX-2 inhibitors, inhibit COX-1 and COX-2.

• Most of these non selective COX inhibiting NSAIDs, including aspirin, are more potent or at least equipotent inhibitors of COX-1 which accounts for some of the more important adverse effects of these drugs.

• Aspirin is an approximately 100-fold more selective inhibitor of COX-1 than COX-2.

Salicylates may inhibit cell migration and some functions of neutrophils.

Salicylates Suppress T cell activity Causes reduction in rheumatoid factor (RF) production.

Other mechanisms contributing to anti-inflammatory effects include reduced capillary permeability, reduced antibody production, and alterations in connective tissue synthesis.

Inhibition of PG synthesis at the site of injury or inflammation can explain at least some of the analgesic effect of aspirin. Although PGs themselves do not seem to cause pain when injected locally, PGE2 and PGF2α do sensitize pain receptors to other mediators such as histamine and bradykinin.

In this connection, aspirin and related drugs can prevent the writhing response elicited by bradykinin but not that produced by PGs. This finding is explained by the fact that the salicylates and all other NSAIDs inhibit the synthesis of PGs induced by bradykinin but not the binding of PGs to their receptors. Animal experiments have revealed that NSAIDs also have central analgesic actions, which may involve the inhibition of COX or other unknown mechanisms at the level of the spinal dorsal horn or at higher levels of the CNS.

Salicylate is distributed throughout most body fluids & tissues. It can be isolated from spinal, peritoneal, and synovial fluids; saliva; breast milk; and sweat.

Salicylate freely crosses the placenta from mother to fetus.

Half-life of sodium salicylate is 2-3 hours after single analgesic dose.

Aspirin

General therapeutic effects

Aspirin has clinically useful analgesic, antipyretic, antiinflammatory, and antiplatelet effects.

1. Analgesic effect sought and attained with aspirin is probably caused in many cases by its anti-inflammatory actions.

Symptomatic relief of acute pain and fever.

Treatment of numerous chronic inflammatory diseases.

2. Antipyretic action

• Fever occurs when the set-point of the anterior

hypothalamic thermoregulatory center is elevated.

• This can be caused by PGE2 synthesis, which is

stimulated when an endogenous fever-producing agent

(pyrogen), e.g: cytokine, is released from white cells that

are activated by infection, hypersensitivity, malignancy, or

inflammation.

• The salicylates lower body temperature in patients with

fever by impeding PGE2 synthesis and release.

3. Antiplatelets effects (anticoagulant effect) Low doses of aspirin can irreversibly inhibit thromboxane (enhances

platelet aggregation) production in platelets.

Because platelets lack nuclei, they cannot synthesize new enzyme, and

the lack of thromboxane persists for the lifetime of the platelet (3-7 days).

As a result of the decrease in TXA2, platelet aggregation is reduced,

producing an anticoagulant effect.

Aspirin also inhibits cyclooxygenase in endothelial cells, resulting in

reduced PGI2 (decreases platelet aggregation) formation

Endothelial cells possess nuclei able to re-synthesize new

cyclooxygenase. Therefore, PGI2 is available for antiplatelet action.

Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology

Blood Vessel WallEndothelial Cell (COX-2)

Ca2+/vessel smooth muscle constricts

Arachidonic acid

PGH2

Prostacyclin (PGI2)

cAMP/vessel smooth muscle relaxes

Arachidonic acid

PGH2

Thromboxane (TXA2)

cAMP aggregation

Ca2+ aggregation

Platelet (COX-1)

• Respiratory actions

At therapeutic doses, aspirin increases alveolar ventilation.

Higher doses work directly on the respiratory center in the medulla, resulting

in hyperventilation and respiratory alkalosis that usually is adequately

compensated by the kidney.

At toxic levels, central respiratory paralysis occurs, and respiratory acidosis

results due to continued production of CO2.

• Gastrointestinal effects Epigastric distress, ulceration, haemorrhage, and iron-deficiency anaemia.

Due to inhibition of PGE2 (stimulate synthesis of protective mucus in both

the stomach and small intestine.

Misoprostol (PGE1-derivative) and the proton-pump inhibitors (lansoprazole,

omeprazole) can also be used for the treatment of an NSAID-induced ulcer.

• Actions on the kidney

Cyclooxygenase inhibitors prevent the synthesis

of PGE2 and PGI2-prostaglandins that are

responsible for maintaining renal blood flow.

Decreased synthesis of prostaglandins can result

in retention of sodium and water and may cause

edema and hyperkalemia in some patients.

USES:1. Acute pain. It is difficult to separate the analgesic

and anti-inflammatory Effects of NSAIDs because most painful

conditions have an inflammatory component.

Aspirin is an effective analgesic for almost any type of acute dental pain.

There is a dose-response for pain relief up to 650 to 1000 mg of aspirin, but increasing the dose beyond these amounts does not enhance the analgesic effect further and does INCREASE the likelihood for toxic effects.

2.Rheumatic fever. One of the early uses of salicylates was in

the treatment of rheumatic fever. Aspirin markedly reduces the acute inflammatory

components of the disease, such as fever, joint pain, swelling, and immobility. Salicylates do not affect other aspects of the disease, however, such as the proliferative reaction in the myocardium leading to scarring, and they do not alter the progression of the disease.

Although anti-inflammatory drugs, including corticosteroids may be used to reduce inflammation, antibiotic therapy is the major therapeutic strategy.

3.Fever4.Prophylaxis against platelet aggregation

5. Rheumatoid arthritis.Salicylates are the drug of choice in the

treatment of rheumatoid arthritis. In larger dose they suppress the swelling,

immobility and redness of the joints involved. They produce relief in pain, swelling and

morning stiffness in the rheumatoid arthritis patients.

Absorption, fate, and excretionWhen aspirin is taken orally, it is rapidly absorbed from the

stomach and small intestine. Aspirin is a weak acid, with a pKa of approximately 3.5, which

favors its absorption in the stomach. Most absorption occurs in the small intestine

Half life : Dose-dependent; 2–3 hours for low doses, 15–30 hours for large doses

Because its acetylation of COX in the platelet is irreversible, however, the full extent of its antiplatelet action depends on the life span of the platelet (8 days) and not on the short half-life of aspirin.

It is quickly metabolized by gastric and plasma esterases to salicylate ion .

Although some aspirin becomes bound to plasma proteins, 80% to 90% of the salicylate ion is bound for a short time, principally to albumin.

The liver is the main site of biotransformation, and conjugation is the primary route.

Adverse effectsDepend on the overall health of the patient, the

length of dosing, and the total daily intake of drug.

• GITEpigastric distress, nausea, and vomiting. Aspirin is an acid and at stomach pH, aspirin is

uncharged; consequently, it readily crosses into mucosal cells, where it ionizes (becomes negatively charged) and becomes trapped, thus potentially causing direct damage to the cells.

• Respiration In toxic doses, salicylates cause respiratory depression.

Allergic reactions include urticaria, skin rash, rhinorrhoea, asthmatic attack and anaphylactic reactions.

• Blood inhibition of platelet aggregation and a prolonged

bleeding time aspirin should not be taken for at least 1 week prior to

surgery.

Contraindications and precautionsDISEASE STATE Possible adverse effect of

aspirin Ulcer Internal bleeding , possible

haemorrhage Compromised liver Function((Hypocoagulation states))

Excessive bleeding

Asthma patientse.g : patients with nasal polyps

Asthmatic attacks resemble allergic reaction

Diabetic High dose may cause hypoglycaemia or hyperglycaemia (Salicylates may also increase insulin secretion)

Gout Low plasma increase plasma urate high dose decrease plasma urate

Children < 16 yrs Reye's syndrome **

viral infection (influneza) in adolescent

Reye's syndrome

aspirin intolerance Allergic reaction

pregnancy and elderly.

Reye's Syndrome :Is primarily a children's disease, although it can occur at any

age. It affects all organs of the body but is most harmful to the

brain and the liver--causing an acute increase of pressure within the brain and, often, massive accumulations of fat in the liver and other organs.

The disorder commonly occurs during recovery from a viral infection, although it can also develop 3 to 5 days after the onset of the viral illness.

Symptoms of RS include 1. persistent or recurrent vomiting.2. Listlessness.3. personality changes such as irritability, disorientation or

confusion delirium, convulsions, and loss of consciousness.

DosageAs analgesic and antipyretic:

0.3-0.6gm, 6-8 hourlyAcute rheumatic fever:

75-100mg/kg/day in divided doses/4-6 days 50mg/kg/day/2-3wks- maintenance dose

Rheumatoid arthritis: 3-5gm/day

Cardio protective: 80-100mg/day

Mild-moderate dental pain: 650 to 1000 mg

.

OverdoseOverdose Acute overdose has a mortality rate of 2% Chronic overdose more lethal with mortality rate 25%

especially in children No antidote for aspirin poisoning.

Acute toxic dose > 150mg/kg Chronic toxicity of doses of 100mg/kg

Lethal dose >500mg/kg Overdose/acute salicylate poisoning is characterized by

salicylism which consists of:1. tinnitus2. vertigo and deafness 3. hyperthermia4. toxic encephalopathy (agitation, confusion and convulsions

followed by coma)5. dehydration (due to hyperpyrexia, sweating and vomiting),6. disturbances of acid base balance 7. petechial haemorrhages.

Treatment of Overdose/Toxicity (Salicylate Poisoning)Treatment

i. Gastric lavage. ii. Intravenous fluid to correct dehydration.

iii. Cold water/alcohol sponges for hyperthermia.iv. To prevent intracellular potassium loss, potassium is given along with sodium bicarbonate.v. For ketoacidosis and hypoglycemia, glucose may be given.

vi. In severe intoxication, dialysis (peritoneal dialysis and haemodialysis) may be used.

Diflunisal is a difluorophenyl derivative of salicylic acid with anti-inflammatory, analgesic, and antipyretic activity. Although structurally related to salicylates but diflunisal is not hydrolyzed in vivo to salicylate and is unique among the salicylates.

Similar to other salicylates, diflunisal blocks the synthesis of PGs by inhibiting COX.

Diflunisal is approximately 10-fold more potent than aspirin in suppressing PG formation in rats.

The drug is well absorbed after oral administration, with peak blood concentrations occurring in 2 to 3 hours. It is highly bound to plasma protein. Diflunisal has a long plasma half-life (8 to 12 hours versus 2.5 hours for salicylate). The drug is excreted in the urine

Diflunisal

USES: 1. Mild-Moderate pain for osteoarthritis 2. rheumatoid arthritis3. postoperative dental painBecause diflunisal has an extended duration of action and a

relatively slow onset of action in acute pain models so the recommended dosage regimen is a 1000-mg loading dose followed by 500 mg every 8 to 12 hours

Adverse Effects4. Nausea and epigastric pain to peptic ulcer and GI bleeding.5. Diflunisal prolongs the prothrombin time in patients

receiving oral anticoagulants, perhaps by competitive displacement of coumarins from protein binding sites.

Note: Diflunisal does not penetrate the blood-brain barrier as well as aspirin does, and diflunisal causes fewer CNS effects, including tinnitus.

For this same reason, it is not used as an antipyretic.

Many NSAIDs chemically unrelated to the salicylates are now available. They all inhibit COX, but they vary in their relative potencies against COX-1 and COX-2.

Some NSAIDs may have other anti-inflammatory actions in addition to inhibiting COX.

For more long-term use, as in the treatment of rheumatoid arthritis, the choice of an NSAID for therapy is largely empiric and often based on what drug is best tolerated and best relieves symptoms in the individual patient. Most of these drugs are arylalkanoic or heteroarylalkanoic acid derivatives.

Other NSAIDs

Possess anti-inflammatory property similar to aspirin but toxicity and adverse effects are fewer and of lesser intensity.

These preparations alone and in combination with other NSAIDs are used for treatment of inflammatory disorders muscle spasm and rheumatic disorders.

They are all well absorbed orally and are highly bound to plasma proteins (90-99%).

Metabolized largely in liver Excreted in urine as well as in bile.Indication : in rheumatoid and osteoarthritis,

ankylosing spondylitis, mild to moderate pain including dysmenorrhoea, soft tissue injuries, fractures and postoperative analgesia.

Propionic acid derivatives

1. Ibuprofen2. Naproxen3. Fenoprofen.4. Oxaprozin.5. Ketoprofen6. Flurbiprofen7. Ketorolac.8. Etodolac9. Sulindac.

Propionic acid derivatives

first single-entity oral analgesic with a greater peak analgesic effect more than 650 mg of aspirin.

Anti-inflammatory, analgesic and antipyretic properties.

Fewer side effects than other NSAID but weaker anti-inflammatory.

Ibuprofen administered preoperatively or immediately postoperatively can delay the onset and lessen the severity of postoperative pain.

Dose: 400 to 600 mg every 4 to 6 hoursMaximum daily dose of 2400 mg.Ibuprofen is a weak organic acid and is highly bound to plasma

albumin. It is extensively metabolized and excreted in urine.Half life of approximately 2 hours. BRUFEN, FENBID, DOLARAZ

1.Ibuprofen:

After oral administration, it is fully Absorbed. It is 99% bound to plasma proteins and crosses

placenta.Partially metabolized , & the metabolites of naproxen

are excreted in urine. Naproxen is more efficacious and better tolerated. It is also longer acting and has the advantage of twice

daily dosing.The sodium salt of naproxen at a 220-mg dose with a

maximum recommended daily dose of 660 mgNaproxen is more irritating to the GI tract than

ibuprofen.

NO PAIN

2. Naproxen

Ketorolac was the first injectable NSAID approved in the United States.

Also available in tablet form for oral use, but only after initial intramuscular or intravenous injection.

The total course of therapy with ketorolac not exceed 5 days. Because the drug’s high incidence of GI ulceration and bleeding complications compared with other NSAIDs.

Indications: in postoperative pain management in patients who are unable to consume oral analgesics or when the pain is severe and injectable opioids are contraindicated.

3.Ketorolac

Adverse effects of propionic acid Although the incidence with some propionic

acid disturbances (epigastric pain, nausea, vomiting, gastric bleeding, and constipation or diarrhea) can occur.

These drugs should be used with caution in patients with a history of peptic or duodenal ulcer.

Long-term, high-dose administration for arthritic conditions is far more likely to produce serious adverse events than short-term administration for acute pain.

CNS effects May include headache, dizziness, drowsiness,

vertigo, and visual and auditory disturbances including tinnitus.

Renal Effects Little effect on normal kidneysNSAIDs Promote Na RETENTION When renal blood flow is impaired as in: Heart failure Dehydration Kidney disease Normal agingSkin rashes are common, and immediate allergic

reactions have been reportedIncreased risk of GI bleeding when these drugs and

other NSAIDs are taken concomitantly with antidepressants of the selective serotonin reuptake inhibitor (SSRI) class.

Name Time to peak (hours)

½ life parent ½ life*active

Aspirin 1-2 0.25-0.33 (*3-10 L-H)

Naproxen 2-4 12-15 Oxaprozin 3-5 42-50*Sulindac (pro-drug) 2-4 7.8

(*16.4) Ketorolac (inj) .5-1 3.8-8.6 Ibuprofen 1-2 1.8-2.5

Pharmacokinetic Variability of Non-Selective COX-Inhibitors

Examples areA. CelecoxibB. rofecoxib, C. ValdecoxibD. KETOROLACE. NIMESULIDEF. NABUMETONE

The selectivity of these so-called coxibs led to roughly a 50% to 60% reduction in serious GI complications—including symptomatic ulcers and GI bleeds, perforations, and obstructions compared with standard NSAIDs (e.g., ibuprofen, naproxen, diclofenac)

Selective COX-2 Inhibitors

Greater affinity for cyclooxygenase-2Decreased incidence of negative effects

associated with non-selective COX-inhibitors

Name Time to peak (hours)

½ life (hours)

Celecoxib 3 11

Rofecoxib 2-3 17

Selective COX-2 Inhibitors cont’

Adverse effects:1. nausea2. vomiting 3. dyspepsia 4. abdominal pain 5. diarrhoea6. edema of the lower extremities

Share some of the renal adverse effects of non selective COX inhibitors and renal toxicity

Hence their use should be restricted to patients who do not tolerate other NSAIDs

Selective COX-2 Inhibitors cont’

Actions 1. Acts on CNS to produce analgesia and antipyretic effect. 2. It also raises the pain threshold.It has negligible anti-inflammatory action peripherally in

therapeutic uses. It is poor inhibitor of PG synthesis in peripheral tissues, but

more active on COX in brain. Paracetamol is given orally and is well absorbed, peak plasma

concentration is reached in 30 to 60 minutes.Excreted in URINEInactivated in LIVER. Acute toxicity may result in hepatic failure.Paracetamol is used for the rapid relief of fever, pains and

aches such as headache, earache, toothache, fibrositis, myalgia, neuralgia, arthralgia, osteoarthritis and postoperative pain.

Para aminophenol DerivativesACETAMINOPHEN/PARACETAMOL

Adverse EffectsThe potential for adverse effects from acute or chronic

overdose with the drug. At therapeutic doses, acetaminophen does not cause nausea,

inhibit platelet aggregation, prolong prothrombin time, or produce the other side affects associated with the use of aspirin or NSAIDs.

Allergy to acetaminophen is rare and is generally manifested as skin eruptions.

Acetaminophen rarely has been associated with neutropenia, thrombocytopenia, and pancytopenia.

In contrast to phenacetin, acetaminophen rarely produce methemoglobinemia

At recommended therapeutic doses (500-1000mg) in healthy subjects is well tolerated

Hepatic and renal toxicity:Larger doses (7-10gm) produce extensive hepatocellular damage

and renal tubular necrosis, and may cause death

This is a major problem in paracetamol poisoning Liver toxicity is due to N-acetyl-P- benzoquinone imine which normally turns

harmless by conjugation with glutathione Early manifestations are just nausea, vomiting, abdominal pain and live

tenderness with no impairment of consciousness After 12-18hrs centrilobular hepatic necrosis occurs which may be accompanied

by renal tubular necrosis and hypoglycemia that may progress to coma

Treatment: Patient is brought early (within 16hrs of ingestion) Vomiting should be induced or gastric lavage done Activated charcoal is given orally or through tube to prevent further absorption Other supportive measures, as needed, should be taken

Specific: N- acetylcysteine 150mg/kg should be infused i.v. over 15min, followed by the

same dose i.v. over next 20hrs

Para aminophenol Derivatives Cont..

Diclofenac:Probably has greater activity than other NSAIDsExtensively bound to plasma proteins, t1/2 is 1-2hrsAccumulates in the synovial fluid- probably responsible

for its longer duration of action than its t1/2

Incidence of adverse reactions is 20%Adverse effects similar to propionic acid derivatives +

elevation of liver enzymes

Arylacetic acid Derivatives

Mefenamic acid:Useful in chronic and dull aching painsNo advantages over other NSAIDsWeaker analgesic than aspirinAdverse reactions include gastric upset, diarrhoea,

dizziness, headache, skin rashes, hemolytic anemia

Dose is 500mg 2-3 times a dayUsed in Dysmenorrhoea

Anthranilic acid Derivatives (Fenamates)

Diclofenac 1% gelIbuprofen 10% gelNaproxen 10% gelKetoprofen 2.5% gelFlurbiprofen 5% gelNimesulide 1% gelPiroxicam 0.5% gel

Topical NSAIDs

DEFINITION:

• Any natural or synthetic compound that imitates properties of natural narcotics

Is an analgesic that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract.

The receptors mediate both the beneficial effects, and the undesirable side effects.

Opoids

ExamplesMorphineHeroinHydromorphoneFentanylCodeine

Natural opiatesAlkaloids contained in the resin of the opium

poppy (morphine, codeine, thebaine)Semi-synthetic opiates

Created from the natural opioids (hydromorphone, hydrocodone, oxycodone,oxymorphone, desomorphine, diacetylmorphine (Heroin)

Fully synthetic opioidsCreated from chemical compounds (fentanyl,

pethidine, methadone, tramadol and propoxyphene)

Endogenous opioid peptides Produced naturally in the body (endorphins,

enkephalins, dynorphins, and endomorphins)

Opoids/ CLASSIFICATION

Distribution - Widely distributed throughout body tissue; concentration in kidney, liver and spleen is higher than that in plasma.

Only a small fraction enters brain rather slowly. Morphine crosses placenta. Metabolism - Extensively in the liver. Excretion - Metabolites are excreted by the kidneys. A small fraction

is excreted in stool through the biliary tract.

Routes of administration - Oral, Transmucosal, I.V (most rapid acting), I.M and S.C

LATENCY TO ONSETi. oral (15-30 minutes)ii. intranasal (2-3 minutes)iii. intravenous (15 – 30 seconds)iv. pulmonary-inhalation (6-12 seconds)

DURATION OF ACTION – anywhere between 4 and 72 hours depending on the substance in question.

Opoids/PHARMACOKINETICS

They reduce pain by binding to receptor sites (mainly mu-receptors) in the central and peripheral nervous system. After stimulation of receptors they mimic the effects of naturally occurring opiates that are apart of the body's own pain relief system.

Processing of pain information is inhibited by a direct spinal effect at the dorsal horn, which involves presynaptic inhibition of the release of tachykinins like substance P.

Emotional response to pain altered by opioid actions on the limbic cortex

Act presynaptically to block Ca2+ uptake and consequently inhibit neurotransmitter release. Opioids have been shown to inhibit the release of many neurotransmitters, including substance P, acetylcholine, norepinephrine, glutamate, and serotonin.

Opoids/PHARMACODYNAMICS

1. relieve severe pain in acute, chronic and

terminal illnesses. 2. Reduce anxiety3. Control diarrhea4. Suppress coughing.

Opoids/PPHARMACOTHERAPUTICS

ACUTE Chronic MiosisRespiratory DepressionNausea and vomitingSedationSkeletal muscle hypertonusEuphoriaConstipationVasodilatationUrinary retentionBradycardiaBiliary SpasmMorphine poisoning

Tolerance Physical Dependence Apnea (in newborns)

Opoids/ADVERSE EFFECTS

1.Sedation and anxiolysisDrowsiness and lethargyApathyCognitive impairmentSense of tranquility

2.Depression of respirationMain cause of death from opioid overdoseCombination of opioids and alcohol is especially

dangerous

3.Cough suppressionOpioids suppress the “cough center” in the brain

4. Pupillary constrictionpupillary constriction in the presence of analgesics

is characteristic of opioid use

Opoids/Pharmacological Effects

5.Nausea and vomitingStimulation of receptors in an area of the medulla called

the chemoreceptor trigger zone causes nausea and vomiting

Unpleasant side effect, but not life threatening

6.Gastrointestinal symptomsOpioids relieve diarrhea as a result of their direct actions on

the intestines

7.Other effectsOpioids can release histamines causing itching or more

severe allergic reactions including bronchoconstrictionOpioids can affect white blood cell function and immune

function

Opoids/Pharmacological Effects cont

OpoidsTolerance and Dependence

Tolerance Tolerance is a diminished responsiveness to the

drug’s action that is seen with many compoundsTolerance can be demonstrated by a decreased

effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect

Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action

This type of tolerance occurs in opioids

DependencePhysiological dependence occurs when

the drug is necessary for normal physiological functioning – this is demonstrated by the withdrawl reactions

Withdrawl reactions are usually the opposite of the physiological effects produced by the drug

Withdrawl ReactionsAcute Action

Analgesia Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Reduced sex drive Flushed and warm skin

Withdrawl Sign Pain and irritability Hyperventilation Dysphoria and depression Restlessness and insomnia Fearfulness and hostility Increased blood pressure Diarrhea Pupillary dilation Hyperthermia Lacrimation, runny nose Spontaneous ejaculation Chilliness and “gooseflesh”

Dependence continuedAcute withdrawl can be easily precipitated

in drug dependent individuals by injecting an opioid antagonist such as naloxone or naltrexone – rapid opioid detoxification or rapid anesthesia aided detoxification

The objective is to enable the patient to tolerate high doses of an opioid antagonist and undergo complete detox in a matter of hours while unconscious

After awakening, the person is maintained on orally administered naltrexone to reduce opioid craving

1.MorphinePHARMACOKINETICSRoutes of administration (preferred) a. Oral latency to onset –(15 – 60

minutes ) b.sniffed c. injected. Duration of action :( 3 – 6 hours) First-pass metabolism results in poor

availability from oral dosing. 30% is plasma protein bound

AGONIST for mu, kappa, and delta receptors.

2. Codeine moderate painSide effect :constipationoral dose; 30-60mg 4-6hrs Max 240mg

3. Dihydrocodeine30-60mg 4-6hrsSide effect : Nausea, vomiting

4.Tramadolopioid effect + enhancement of seratogenic and

androgenic pathways.less opioid side effects.psychiatric rxns reportedDose 50-100mg 4-6hrs.

5. Pethidineprompt short term analgesia.less constipating than morphine less potent analgesic50-150mg 4-6hrs.sc or IM 25-100mg 4-6hrs.

Nonopioids Aspirin and acetaminophen are sometimes combined in

proprietary compounds. There is little evidence that either analgesia or antipyresis is

enhanced by this combination. A ceiling effect still occurs when the total amount of aspirin and

acetaminophen approaches 1 g. In pain following impacted third molar surgery, the combination

of 100 mg of enteric-coated diclofenac with 1000 mg of acetaminophen provides a superior analgesic effect than either drug alone or combination of 1000 mg of acetaminophen plus 60 mg of codeine.

Many of these combinations also contain caffeine. Caffeine is considered to be an analgesic adjuvant.

Caffeine doesn't seem to have analgesic effects when used alone. When 65to 100 mg of caffeine is combined with traditional analgeics (aspirin, acetaminophen, or ibuprofen), it improves their analgesic efficacy.

COMBINATION ANALGESICS

Opioid and Nonopioid Analgesics

Combination between NSAIDs or acetaminophen with opioids. NSAIDs/acetaminophen combat pain principally by interfering

with production of biochemical mediators that cause sensitization of nerve endings at the site of injury or spinal cord, whereas the opioids alter CNS perception and reaction to pain.

The clinical significance of the opioids is1. They provide additional analgesia beyond the ceiling effect

of the NSAID or acetaminophen alone2. They contribute a centrally mediated sedative effect.

The most effective combinations are those that use the optimal amount of an aspirin-like drug combined with the appropriate dose of an opioid analgesic.

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