V. Analgesic-antipyretic drugs Aspirin-like drugs Mediators of inflammation: I. Plasma-derived: 1. Clotting-fibrinolytic system : fibrin split products. 2. Kallikrein-kinin system : Kinins.

3. Complement system: C3a, C5a. II. Cell-derived: 1. Mast cells, basophils: histamine. 2. Platelets : serotonin. 3. Inflammatory cells : PGs, Leukotrienes, PAF. 4. Macrophages, lymphocytes, endothelial cells, fibroblasts: cytokines. All are vasoactive mediators that increase, directly ore indirectly, increase vascular permeability. Cytokines 1. Different peptides. 2. Produced mainly from macrophages and lymphocytes. 3. Regulate inflammatory and immune reactions. 4. Main cytokines are: a) Interleukin 1 to 8 b) Interferons. c) Tumor necrosis factor d) Various colony stimulating factors.

Mechanism of action of NSAIDs 1. The main postulated mechanism is inhibition of cyclooxygenase enzymes (COX). This can be: A) Rapid, reversible, competitive inhibition of COX, as propionic acid derivatives. B) Rapid, reversible, non-competitive inhibition of COXas fenamates. C) Slow, irreversible inactivation as aspirin. 2. Most NSAIDs block both COX-I and COX-II. Others as meloxicam show a variable and always incomplete degree of selectivity. 3. Since COX-II is the isozyme thought to be responsible for the production of inflammatory PGs, efforts to develop selective COX II inhibitors are underway. The block of cyclooxygenase leads to the inhibition of PG biosynthesis (but not of leukotrienes biosynthesis. Other postulated mechanisms include inhibition of: a) Superoxide generation (diclofenac, piroxicam). b) Leucocyte migration (naproxen). c) Leukotriene production (diclofenac, ketoprofen). d) Transmembrane ion transport. e) Cartilage metabolism. f) Lysosomal enzymes.

Analgesic effect of NSAIDs: 1. The effect is evident in pain due to inflamed tissues (arthritis), surgery, dysmenorrheal, bone metastases, toothache, headache (some kinds). 2. The effect is low or even absent in severe ischemic and visceral pain. 3. The intensity of analgesic effect is generally lower than that obtained by opioids and is not linked to a change in the affective response to pain. 4. The analgesic effect does not undergo tolerance. 5. Mechanisms include inhibition of PG-induced sensitization of peripheral pain receptors and of PG mediated inflammatory processes. A central depressive action likely at the hypothalamic level is also postulated.

Anti-inflammatory Effect of NSAIDs: 1. NSAIDs inhibit mainly the early phase of inflammatory reaction (vasodilation, increased vascular permeability, oedema..) 2. NSAIDs have only limited effects on cellular accumulation either in acute or chronic inflammation. 3. NSAIDs have negligible effects on the proliferative phase of inflammation (fibrotic repairing is not affected). 4. NSAIDs have no direct effects on the specific immunological response. The postulated mechanisms include: A) Inhibition of PG and thromboxane biosynthesis. B) Stabilization of lysosomal membranes (thus preventing the escape of lysosomal enzymes into the cytoplasm). C) Inhibition of plasmin, a plasma proteolytic enzyme which may activate kinin formation. D) Inhibition of the activation and function of neutophils, macrophages and mast cells.

Pharmacodynamics of salicylates: 1. CNS: a) After moderate doses: central antipyretic effect. b) After high doses: stimulation of CRTZ 2. Respiratory system: a) After moderate doses: negligible effect. b) After high doses: stimulation of respiration indirectly by increased production of CO2 and directly by a direct effect on the respiratory center in the medulla oblingata. c) After very high doses: direct depression of the respiratory center. 3. CVS: a) After moderate doses: negligible effect. b) After high doses: direct dilating effect on peripheral blood vessels and increase of circulating plasma volume.

4. Urinary system: A) After moderate doses: Small increase in GFR. Blockade of tubular uric acid excretion. B) After high doses: A) Decrease in GFR mainly in patients with cardiac failure, renal disease and hypovolemia.

B) Blockade of tubular uric acid reabsorption. C) Increased Na+ and K+ reabsorption. D) Increased water reabsorption E) After chronic doses (2-3 years of treatment): renal lesions

5. Hematopoietic system: A) After moderate doses: Decreased platelet aggregation (the effect can last 7-8 days) (cyclooxygenase blockade reduces both the production of TXA2 which promotes aggregation and of PGI2 which inhibits aggregation. However, endothelial cells produce new cyclooxygenase in a matter of hours while platelets cannot manufacture the enzyme). B) After very high doses: hypoprothrombinemia. 6. GIT: a) Stomach:erosive gastritis. b) liver: direct stimulation of bile secretion by hepatocytes, dose-dependent hepatic damage, severe hepatic injury (in Rey's syndrome). 7. Endocrine system: After high doses: Increased ACTH secretion, stimulation of adrenaline release. 8. Acid-base balance: After high doses: 1. Uncoupling of oxidative phosphorylation in skeletal muscle which leads to hyperthermia.

2. Hypoglycemia due to stimulation of insulin secretion or hyperglycemia and glycosuria due to adrenaline release and to increased glycogenolysis. 3. Hyperkalemia due to increased K+ reabsorption by the kidney. Salicylate toxicity: A) Side effects Dyspepsia, urticaria, angioneurotic edema, laryngeal edema and shock.

B) Overdosage toxicity: a) Mild intoxication (salicylism). 1. Plasma salicylate concentration (400-800 mcg/mL). 2. Headache, dizziness, tinnitus, difficulty in hearing, mental confusion, sweating, hyperventilation, nausea, vomiting and diarrhea.

b) Serious intoxication 1. Plasma salicylate concentration greater than 800 mcg/mL. 2. tinnitus, vertigo, diplopia, respiratory depression, tremors, delirium, hallucinations, generalized convulsions and coma. Nausea, vomiting, abdominal cramps, gastric bleeding. Acidosis, marked hyperthermia, dehydration, hyperglycemia, hypoglycemia in children, hypoprothrombinemia.

C) Adverse effects after chronic treatment: 1. Chronic erosive gastritis. 2. Increased incidence of peptic ulcer 3. Analgesic nephropathy. 4. Liver diseases. 5. Hemolytic anemia in patients with G6PD. 6. Hypochromic anemia 7. Rey's syndrome in children. 8. Salicylism. 9. Toxicity in pregnancy: 10. Increased occurrence of abortion, prolonged labor. 11. Pre and postpartum hemorrhage. 12. Hemostatic abnormalities in the newborn.

Aspirin hypersensitivity: 1. Vasomotor rhinitis, urticaria, bronchoconstriction, angioneurotic edema, laryngeal edema, vascular shock, the reaction can be lethal. 2. The reaction does not appear to be immunological in nature and therefore it is a paeudoallergic reaction. It seems to be related to the formation of increased amount of leukotrienes

and other products of lipooxygenase pathway, due to inhibition of cyclooxygenase pathway. 3. There is cross sensitivity between aspirin and other NSAIDs and therefore the hypersensitivity to aspirin is a contraindication to the therapy with any NSAIDs.

The Rey's Syndrome: 1. Mainly in children or young adults. 2. Fatty infiltration of liver and other organs as pancreas, heart, kidney as well as cerebral edema. 3. The syndrome develops in two phases: A) Respiratory depression. B) After 4-days: nausea, vomiting, sudden change in mental status, liver damage.

Therapeutic uses of salicylates: 1. Local uses: A). Keratolytic agents. B). Counterirritant. 2. Systemic uses: A). Antipyresis. B). Analgesia.

C) Inflammatory diseases as acute rheumatic fever, rheumatoid arthritis, ulcerative colitis. D) Thromboembolic diseases as myocardial infarction, unstable angina, cerebrovascular disorders.

Contraindications 1) Gastritis, gastric and duodenal ulcer. 2) Other ulcerative diseases of the upper GIT 3) Alcohol consumption. 4) Methotrexate toxicity. 5) Coagulation disorders as hemophilia, hypoprothrombinemia. 6) G6PD deficiency. 7) Decreased hearing capacity or administration of ototoxic drugs. 8) Renal insufficiency. 9) Advanced heart failure. 10) Severe hypertension. 12) Serious hepatic disease. 13) Asthma, hay fever, nasal polyps, urticaria. 14) NSAIDs hypersensitivity.

15) Viral febrile illness in children. 16) Pregnancy.

Classification of NSAIDs 1) Salicylates as Aspirin. 2) Arylalkanoic acids as Diclofenac, Ketorolac, Indomethacin, Sulindac. 3) Arylpropionic acids (Profens) as Ibuprofen, Ketoprofen, Naproxen, Tiaprofenic acid. 4) N-arylanthranilic acids (fenamic acids) as Mefenamic acid. 5) Pyrazolidine derivatives as Phenylbutazone, oxyphenbutazone. 6) Oxicams as Piroxicam, Tenoxicam, Meloxicam 7) COX-2 inhibitors as Celecoxib, Rofecoxib . 8) Sulphonanilides as Nimesulide. 9) Others as Omega-3 fatty acids.

Characteristic features of other NSAIDs 1) The analgesic, antipyretic, anti-inflammatory and antiplatelet effects are qualitatively similar to aspirin. 2) The efficacy of some compounds as analgesic agents (Ketorolac) or anti-inflammatory agents (Indomethacin, Diclofenac) seems higher than others 3) GI and CNS effects are less than those of aspirin. 4) Effects on acid/base balance or uric acid secretion are minimal compared to aspirin.

Mechanisms of action of different NSAIDs 1) COX-1 inhibition as aspirin, indomethacin, sulindac, and piroxicam. 2) Equal COX-1 and COX-2 inhibition as Ibuprofen, naproxen and Diclofenac. 3) Mainly COX-2 inhibition as Meloxicam 4) Inhibition of leucocyte migration as Naproxen. 5) Inhibition of production of H2O2 by activated neutrophils as Diclofenac, Piroxicam. 6) Inhibition of leukotriene production as Diclofenac, Ketoprofen.

Important information about Acetaminophen: 1) It is a very weak, reversible, non-competitive inhibitor of COX in vitro, or in inflamed tissue. 2) It is a good COX inhibitor in the CNS. 3) Analgesic and antipyretic effects are qualitatively similar to those of other NSAIDs. 4) Antiinflammatory effect, inhibition of platelet aggregation, gastric erosion, and bleeding, decreased Na+ and water clearance are absent. 5) There is some speculation that Paracetamol acts through inhibition of COX-3 isoform 6) It has negligible anti-inflammatory activity and so it is not an NSAID.

Clinical pharmacology of NSAIDs: 1) Aspirin remains the prototype of NSAIDs. 2) None of the newer NSAIDs proved more effective than aspirin in controlled studies. 3) Aspirin however is less safe than other NSAIDs (at least in the GIT) and it has been largely replaced by ibuprofen. 4) In patients prone to develop peptic ulcer who are taking aspirin, PGE2 analogue (Misoprostol) may be used (unfortunately the drug causes diarrhea in many patients). 5. Patients who develop adverse effects from one NSAID may be treated with another NSAID belonging to a different group.

6) The newer NSAIDs have been responsible for many instances of acute renal failure and nephritic syndrome which is neither dose-dependent nor time-dependent. 7) The choice of a NSAID in an individual patient remains an empirical issue as it is not possible to know which patient will respond in a specific way to which NSAIDs, some patients deive benefit from one and not from another.

Uses of NSAIDs: 1. Treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for colorectal cancer, and treatment of other conditions such as cancer and cardiovascular disease. 2. NSAIDs are generally indicated for the symptomatic relief of the following conditions: 1) Rheumatoid arthritis. 2) Osteoarthritis. 3) Inflammatory arthropathies as ankylosing spondylitis. 4) Acute gout. 5) Dysmenorrhea. 6) Metastatic bone pain. 7) Headache and migraine. 8) Postoperative pain. 9) Mild to moderate pain due to inflammation and tissue injury.

10) Pyrexia. 11) Renal colic. 12) Aspirin, the only NSAID able to irreversibly inhibit COX1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse CV events. Pharmacokinetics of NSAIDs: 1) Most NSAIDs are weak acids and they are absorbed well from the stomach and intestinal mucosa. 2) They are highly protein-bound in the plasma usually to albumin, so that their Vd typically approximates to plama volume. 3) Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites which are excreted in the urine. Some drugs are patially excreted in bile. 4) Metabolism of NSAIDs may be abnormal in certain disease states, and accumulation may occur even with normal dosage. 5) Ibuprofen and Diclofenac have short half-lives (2-3 hours). Some NSAIDs (oxicams) have very long half-lives (20-60 hours).

Adverse Effects: 1) The main ADRs associated with the use of NSAIDs relate to direct and indirect irritation of GIT. NSAIDs cause a dual effect on the GIT- the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins. 2. Common gastrointestinal ADrs include * Nausea and vomiting. * Dyspepsia. * Gastric ulceration and bleeding. * Diarrhea. 3. Risk of ulceration increases with duration of therapy, and with higher doses. It is possible to minimize Gi ADRs by using the lowest effective dose for the shortest period of time. 4) Indomethacin, ketoprofen and piroxicam appear to have the highest GI ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of GI ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates. 5) Certain NSAIDs as aspirin have been marketed in entericcoated formulations to reduce the incidence of GI ADRs. 6) GI ADRs can be reduced by suppressing acid production by concomitant use of a proton pump inhibitor as omeprazole or PG analogue as misoprostol, however, misoprostol may be associated with diarrhea. These techniques prove to be expensive for maintenance therapy. 7) High incidence of renal ADRs are present probably due to changes in renal blood flow ordinarily mediated by PGs, and affected by NSAIDs

Common effects include salt and fluid retention and hypertension. 8) These agents may cause renal impairment, especially in combination with other nephrotoxic agents. 9) Renal failure is a risk if the paient is concomitantly taking an ACE inhibitor and a diuretic (triple whammy effect). 10) In rare instances, NSAIDs may cause more severe renal conditions as: * Interstitial nephritis. * Nephrotic syndrome. * Acute renal failure. * Acute tubular necrosis. 11) Photosensitivity is commonly an adverse effect of many NSAIDs. These drugs may produce inflammation in combination with exposure to sunlight.. (Benoxaprofen was withdrawn due to its hepatotoxicity, also was the most photoactive NSAID 12) During pregnancy: * Not recommended during pregnancy especially during the third trimester Why? - They may cause premature closure of the fetal ductus arteriosus and renal ADRs in the fetus. - They are linked with premature birth. - Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies. - Incontrast, paracetamol is safe during pregnancy. 13) Doses of NSAIDs should be taken as prescribed due to risk of hepatotoxicity with overdoses. 14) Other common ADRs include raised liver enzymes headache and dizziness.

15) Uncommon ADRs include heart failure, hyperkalemia, confusion, bronchospasm, rash. Ibuprofen may also rarely cause irritable bowel syndrome symptoms. 16) Most NSAIDs penetrate poorly into the CNS. However, COX enzymes are expressed in some areas of the CNS meaning that even limioted penetration may cause adverse effects such as somnolence and dizziness. Selective COX inhibitors: 1) COX-1 regulates many normal physiological processes. One of these is in the stomach lining, where PGs serve a protective role, preventing the stomach mucosa from being eroded by its own acid. 2) When non-selective COX-1/COX-2 inhibitors such as aspirin, ibuprofen and naproxen lowers stomach PGs levels, these protective effects are lost and ulcers of the stomach or duodenum and internal bleeding can result. 3) COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. 4) Oxicams, meloxicam was considered relatively selective COX-2 inhibitor while Coxibs are true COX-2 selective inhibitors as celecoxib, rofecoxib, valdecoxib. 5) Controversies with COX-2 inhibitors: the clinical data showed no significant difference in ADRs with celecoxib when compared with diclofenac. 6) Inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever as in case of paracetamol. END OF THE LECTURE

VI. OPIOID ANALGESICS

Opium: an extract from the juice of the unripe seed capsules .(of papaver somniferum (opium poppy .Opiate: a drug with close structural similarity to morphine .Opioid: any substance that produce morphine-like effects :Narcotic In the past applied to any drug that produces drowsiness, .1 .analgesia and a detached feeling For a number of years, used to refer to morphine-like .2 analgesics In the legal sense, narcotic is any drug included under .3 .Federal Narcotic Laws

?What are opioid receptors Include Mu, Kappa, Delta and Sigma receptors .1 Exert inhibitory modulation of synaptic transmission in .2 .both the CNS and the mysenteric plexus Often found on presynaptic nerve terminals, where their .3 action results in a decreased release of a large number of .neurotransmitters They are coupled to an inhibitory guanine nucleotide .4 .(binding protein (Gi protein :Main transduction mechanisms of all these receptors are .5 A) Opening of ligand-gated K+ channels on postsynaptic .neurons B) Blockade of voltage-gated Ca++ channels on presynaptic nerve terminals .C) Inhibition of adenylyl cyclase activity

TYPES OF OPIOID RECEPTORS & THEIR LIGANDS RECEPTOR TYPE Mu receptors ((Mu1, Mu2 Kappa receptors ((K1 and K3 Delta receptors, Delta1 and 2 Sigma receptors ENDOGENOUS LIGANDS B-endorphin Dynorphin A Met-enkephalin ? EXOGENOUS LIGANDS Morphine Ethylketociclazocine Etorphine N-allyl.normetazocine

PHARMACOLOGICAL CLASSIFICATION OF OPIOIDS :AND OPIOD ANTAGONISTS CLASS AGONISTS PARTIAL AGONISTS MIXED AGONISTSANTAGONISTS ANTAGONISTS DRUG MORPHINE, CODEINE, HEROIN PENTAZOCINE BUTORPHANOL NALOXONE, NALTREXONE

:ORGAN SYSTEM EFFECETS OF MORPHINE :CNS EFFECTS .1 .Analgesia .1 .Euophoria .2 .Sedation .3 .Excitatory CNS effects .4 Poikilothermia .5 .Respiratory depression .6 .Cough suppression .7 .Miosis .8 Nausea and vomiting .9

:PERIPHERAL EFFECTS .2 :A) GIT EFFECTS .Decreased peristalsis .1 .Decreased secretions .2 .Increased tone of smooth muscle .3

:B) CV EFFECTS .Vasodilation .1 .Inhibition of baroreceptor reflexes .2

:C) OTHER SYSTEMS Increased tone of detrusor and sphincter of the urinary .1 .bladder Decreased release of CRF and GnRH .2

ANALGESIC EFFECT OF MORPHINE All types of pain (superficial and deep, somatic and .1 .visceral) can be effectively relieved by opioids The relief of pain is relatively selective (other sensory .2 .modalities are not affected by usual therapeutic doses Continuous dull pain is relieved more effectively than .3 .sharp, shooting, intermittent pain Nociceptive pain (pain transmitted over intact neural .4 .pathways) is effectively relieved Neuropathic pain (pain caused by damage of neural .5 .structures) often respond poorly to opioids Opioids exert the analgesic effect by lowering of pain .6 perception (the pain threshold is raised) and but moderate .effects on pain threshold Another component of the analgesic effect is the allay of .7 .suffering and discomfort associated with pain perception :Mechanisms of analgesic effect of morphine .8 A) Inhibition of release of excitatory neurotransmitters, including substance P, from the terminals of afferent nerves .in spinal cord B) Inhibition of nociceptive transmission in lateral .spinothalamic tract C) Activation of descending aminergic bulbospinal pathways which exert inhibitory effects on the processing of .nociceptive information in the spinal cord

PSYCOLOGICAL EFFECTS OF OPIOIDS A foggy, unreal feeling of being detached from things .1 .((mainly things that cause distress Euophoria (a pleasant, relaxed, dreaming state) which is .2 more common when opiods are given to a patient with pain or to addict Dysphoria (a feeling of general malaise with difficulty of .3 mentation and apathy) which is more common when opioids .are given for the first time to a normal, pain-free person A "Kick" or "thrill" (a sensation in the lower abdomen .4 similar in quality to sexual orgasm) when given to an addict .by rapid IV injection A period of sedation and tranquility ("on the nod") which .5 .follows the "kick" and lasts about one hour .Decreased drives such as hunger, thirst and libido .6 Dose-dependent sedation (decreased physical activity) and .7 .drowsiness .Very high doses of opioids can cause unconsciousness .8

:RESPIRATORY EFFECTS OF MORPHINE All phases of respiratory activity are depressed (rate, .1 .(minute volume and tidal exchanges Respiratory depression is detectable even at subanalgesic .2 .doses and is dose-dependent :The main mechanisms of respiratory depression .3 A) Reduce the sensitivity of the respiratory centers (in .brainstem) to P CO2 B) Depress the centers in the pons and in the medulla (pneumotaxic and apneustic centers) that regulate the .rhythmicity of breathing Depression of cough reflex partly due to depression of .4 cough center .Bronchoconstriction with large doses .5

:CARDIOVASCULAR EFFECTS OF MORPHINE .Arteriolar and venous dilation .1 :The mechanisms of vascular dilation include .2 .(A) Histamine release (the main mechanism .(B) Depression of vasomotor system (slight C) Hypercapnia due to respiratory depression (with large .(doses .Depression of baroreceptor breflexes .3 .Slight decrease in heart rate .4

All the above mentioned effects can induce orthostatic .5 hypotension. CV effects are not prominent in normal .individuals

:GASTROINTESTINAL EFFECTS OF MORPHINE Marked increase in tone of smooth muscle (sphincteral .1 .(and non-sphincteral Marked increase in amplitude of nonpropulsive .2 contractions but marked decrease in amplitude of .propulsive contractions Decrease in gastric, pancreaticm, biliary, intestinal .3 secretions .Nausea and vomiting .4

TOLERANCE TO THE EFFECTS OF MORPHINE The rate of tolerance development depends on the pattern .1 .of opioid use .Tolerance does not develop to all effects of opioids .2 There is a high degree of cross-tolerance among opioids .3 acting on the same receptor type but no cross-tolerance .among opioids acting on different receptors .Tolerance is mainly functional (or cellular) in nature .4 Minimal or no tolerance developed to miosis, constipation, .5 .convulsions and antagonist actions

:MORPHINE PHARMACOKINETICS .Oral bioavailability is 25% due to large first-pass effect .1 .Rectal bioavailability may be higher .2 Intramuscular bioavailability is 95% .3 .(Bound to plasma proteins (35% .4 .Distributed mainly in kidneys, liver and lungs .5 is conjugated with glucuronic acid mainly in the liver 90% .6 and gut wall to form morphine-3-glucuronide (inactive) and .(morphine-6-glucuronide (active excreted by the kidney and trace amounts by sweat, 10% .7 .saliva and milk Half-life of morphine is 2 hours and morphine-6- .8 .glucuronide is 3 DIFFERENCES BETWEEN MORPHINE AND OTHER OPIOIDS :Various opioids may differ from morphine in Potency .1 .Pattern of effects .2 .Duration of analgesia .3 .Clinical efficacy .4 .Oral bioavailability .5 Abuse liability .6

THERAPEUTIC USES OF MORPHINE Acute pain due to trauma, burns, surgery, labor, colic, .1 .acute pancreatitis and myocardial ischemia .(Chronic pain due to terminal illness and cancer .2 .Acute pulmonary edema .3 .Cough when it is non-productive and disturbing .4 .Diarrhea when it is exhausting and dehydrating .5 :Applications in anesthesia .6 .A) Premedication before anesthesia B) Primary component in anesthetic regimen in certain .surgical procedures .C) As regional analgesic when given into the epidural space :Opioid resistant pains include .7 .A) Neuropathic pains as post-herpetic neuralgia .B) Skeletal muscle spasm .C) tension headache .D) Increased intracranial pressure END OF THE LECTURE