Non Steroidal Antiinflammatory Drugs - PowerPoint Presentation

1. Non Steroidal Antiinflammatory Drugs NSAIDs All cells in the body have the capacity to synthesize prostaglandins. In response to inflammatory stimuli arachidonic acid (AA) is formed from plasma phospholipids by phospholipase A2. Cyclooxygenase metabolizes AA to the cycloendoperoxide (prostaglandin H2) (PGH2), which is then converted to either PGD2, PGE2, PGF2α, PGI2 (prostacyclin) or TXA2 (thromboxane) by appropriate enzymes (i.e. PG isomerase, thromboxane synthase in platelets, prostacyclin synthase ).

2. Prostaglandins exert numerous physiologic and pathophysiologic effects: -Pathologic: fever, inflammation, pain, asthma, ulcers, diarrhea , dysmenorrhea. -Physiologic: temperature, bronchial tone, cytoprotection (gastric and renal mucosa), intestinal mobility, myometrial tone, semen viability (some prostaglandins like PGE1 have anti-inflammatory effects), renin secretion, renal vascular tone, homeostasis.

3. There are two forms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. -COX-1 produces PGE2, PGI2, and TXA2 in platelets, GI mucosa, vascular endothelium, and the kidney. The housekeeping functions of these prostaglandins include maintaining renal and gastrointestinal blood flow (cytoprotection), regulation of vascular homeostasis, renal function, intestinal mucosal proliferation, and platelet function. -Pro-inflammatory functions of COX-2 produced prostaglandins include pain, fever, leukocyte proliferation, and inflammation. COX-2 produces prostaglandins at sites of inflammation (in macrophages, in synovial tissue of rheumatoid arthritis joint). Mitogenic functions of COX-2 produced prostaglandin include renal genesis and reproduction.

4. NSAIDs included:1-Non specific ( COX-1 and COX-2) Inhibitors-Salicylates: aspirin: salicylic acid, methyl salicylic acid, 5-aminosalicylate, sodium salicylate, magnesium salicylate, sulfasalazine, olasalzine-Propionic acids: ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin-Acetic acids: indomethacin, diclofenac, sulindac, etodolac, ketorolac, tolmetin-Fenamic acids: meclofenamate, mefenamic acid-Enolic acids (oxicam class): piroxicam, phenylbutazone-Para- amino Phenolic acids: Paracetamol2- specific ( COX-2) Inhibitors:Coxibs and Meloxicam

5. All NSAIDs (except aspirin) act as reversible, competitive cyclooxygenase inhibitors. They block the hydrophobic channel by which the substrate arachidonic acid accesses the enzyme active site. Aspirin covalently modifies and destroys the cyclooxygenase enzyme. The function of the NSAID is to inhibit COX-2, preventing generation of proinflammatory eicosanoids, and thus limiting the extent of inflammation and adverse signs and symptoms. NSAIDs have three primary therapeutic effects: (Analgesia, Anti-pyrexia, Anti-inflammatory) -NSAIDs are also used as anti-thrombotics. Since they impair platelet aggregation, they prolong bleeding time, and function as anticoagulants. The COX-2 specific inhibitors do not exert anti-thrombotic effects.ƒ

6. SalicylatesAcetylsalicylic Acid (Aspirin)It is a salicylate that used to relieve headaches, muscular and joint pains, and reduces inflammation.The drug is rapidly absorbed by oral route, and primarily absorbed in the stomach and upper small intestine. Peak level is within 15 minutes to 2 h.If gastric PH is raised by suitable buffer to 3.5 or higher gastric irritation will be minimized (less absorption and less irritation).After absorption of aspirin it is hydrolyzed into acetic acid and salicylates, salicylate binds to albumin but as serum conc. of salicylates increases, a greater fraction remain unbound and available to tissue.Ingested salicylates and that generated by hydrolysis of aspirin may excreted unchanged, but most is converted to water soluble conjugates that are rapidly cleared by the kidney. When this pathway becomes saturated, a small increase in aspirin dose result in large increase in plasma level.Urine alkalinization will prevent reabsorption of salicylates. Actions:Antiinflammatory, antipyretic , analgesic and anti-platelete effects The mechanism of action of Aspirin: inactivates cyclooxygenase irreversibly, it inhibits formation of PGs and TXs (TXA2). It also interferes with chemical mediators of Kallikrein synthesis. It also inhibits granulocytes adherence to damaged vasculature and stabilizes lysosomes and inhibits migration of poly morpho neutrophlils (PMN) and macrophages to site of inflammation.Other effects:Respiratory Effect:Therapeutic does increase alveolar ventilation, higher does acts directly on respiratory centre (in medulla) causing hyperventilation and respiratory alkalosis, toxic dose cause central respiratory paralysis and metabolic acidosis, due to continuous CO2 production.GIT:PGI2 inhibits gastric secretion, PGE2 stimulates synthesis of protective mucosa in the stomach and intestine. Aspirin ↑ acid secretion and ↓ mucus production→ ulceration.Renal effects:PGI2 and PGE2 which are responsible for maintaining normal renal blood flow, using of Aspirin cause peripheral nephropathy and Na+ and water retention causing edema and hypokalemia in some patients.

7. Indications:Used for pain, fever, inflammatory conditions such as rheumatic fever, rheumatoid arthritis, osteoarthritis, and symptomatic relief of the common cold pain and fever. It is used for reducing the risk of recurrent Transient Ischemic Attacks (TIA/stroke), or Myocardial Infarctions (MI/heart attack) at low doses.Dosage form: Tablets and Injection. Doses: 350 - 650 mg / 4 h. for minor pain. 500 - 1000 mg / 4-6 h.; max. 4 g/24 h., for moderate to severe pain.75-325 mg/day continued indefinitely for: Ischemic stroke & TIA, and the prevention of recurrent MI, unstable angina pectoris, chronic stable angina pectorisSide effects: Dizziness, cinchonism (ringing in the ear), skin eruptions, epigastric discomfort, peptic ulceration and bleeding, increase bleeding tendency, hypersensitivity reactions. Aspirin given to children during viral infection causes increased incidence of Reye's syndrome (fatal hepatitis with cerebral oedema) (Acetaminophen is used instead of Aspirin in children). Overdose: Can be fatal, particularly in children. Acute lethal dose is approximately 10-30 g for adults, and 4 g in children. Requires immediate referral to hospital. It presents with confusion, rapid deep breathing, sweating, tinnitis (noises in the ear), deafness followed in severe cases by unconsciousness.Treatment: Induce vomiting if possible (patient is conscious). Activated charcoal decreases absorption if given within 2 hrs after ingestion.Contraindications: In patients with history of hypersensitivity, asthma, peptic ulcer/dyspepsia, those with bleeding tendencies or disorders.-Not to be taken on an empty stomach. -Avoid ASA for at least 1 week prior to surgery. - Patients should inform the dentist or doctor of taking this medication before doing any lab or dental work. -Avoid alcohol while taking this medication since it increases the GI ulceration. Contraindicated in hemophilia patients and in pregnancy ( fetal malformation)External uses of other salicylates:Salicylic acid ( Whitefeild ointment) is used topically as keratolytic andin the treatment of corns and.Methyl salicylic acid (oil of wintergreen) is used externally as ointment as counter irritant in ointments

8. Propionic acidsIbuprofenIbuprofen is comparable to aspirin in its analgesic action, but higher doses are required for anti-inflammatory effect. It has less GI symptoms than aspirin in equi-effective doses. It inhibits platelet aggregation and prolongs bleeding time, but does not affect prothrombin or whole blood clotting times.80% of the drug is absorbed from the GI tract. Peak effect is 1-2 h. , Onset for analgesia is 0.5 h., and for antirheumatic action is 7 days.Indications:Rheumatoid arthritis, osteo arthritis, mild to moderate pain, primary dysmenorrhea, fever. Dosage form: Tablets, suspension (100mg/5ml), gel 5%. Dose: Adult: 200-400 mg PO/4-6h, max. 1800 mg/24 hours for pain and fever. 400-800 mg t.i.d. or q.i.d.; max. 3200 mg/d for inflammation.Side effects:GI disturbances are most common; i.e. heartburn, nausea and dyspepsia, abdominal distress, gastritis and ulceration. Also, dizziness, drowsiness, jaundice, and fatigue may occur. Side effects are dose related.Naproxen- rapidly absorbed from GIT, antacids delay its absorption, Binds to plasma protein, t1/2 = 13 hrs. - Excreted in urine as inactive glucuronid metabolites.- Competes with aspirin for plasma protein binding sites & it prolong prothrombin time.- Indicated in: Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis, Mild to moderate pain, Primary dysmenorrheal, Juvenile rheumatoid arthritis , arthritis , Tendinitis, Bursitis and Acute gout- Average doses for inflammatory arthritis is 375 mg twice a day.Side effects: less incidence than that of aspirin and indomethacin ( GIT,CNS, pruritis and dermatological problems)

9. Acetic acid derivativesIndomethacinA very potent acetic acid NSAID derivative. Because of its high potential to cause side effects when used in high doses, it should be carefully considered for active disease unresponsive to adequate trials with salicylates. It has equal or a little superior action than naproxen, but higher incidence of side effects. This medication will enable reduction of steroid doses in severe forms of Rheumatoid Arthritis.Indications:Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis, Tendinitis, Bursitis , Acute gout, Acute painful shoulder. not suggested for general use as analgesic. It is used in the treatment of patent ductus arteriosus.Dosage forms: Capsules, suppositories, gel.Dose: Adult: Rheumatoid Arthritis: 25-50 mg b.i.d. or t.i.d., or 75 mg sustained release 1-2 times a day; max. 200 mg/d. Acute Gout: 50 mg t.i.d. until pain is tolerable (usually within 2-3 days), then 25 mg t.i.d. until total resolution of attack. Child: Not recommended, but used for Patent Ductus Arteriosus in premature infants.Adverse effects: Same as Ibuprofen , but with higher incidence

10. Diclofenac:It has analgesic, antipyretic, and anti-inflammatory properties. At therapeutic doses it has little effect on platelet aggregation. It has analgesic, antipyretic, and anti-inflammatory properties.Diclofenac is readily absorbed from the GI tract, and 50-60% reaches the systemic circulation. Peak effect is within 2-3 h.Indications: Rheumatoid arthritis , Osteo arthritis, Ankylosing spondylitis.Dosage form: Tablets, sustained release tablets, suppositories, gel and ampoules.Dose: Adult: 75-150 mg/24h given by mouth in divided doses. Total daily dose should not exceed 150 mg/d. Suppository form is given in a dose of 75-100 mg each evening. The gel form 1% should be applied to painful site, 2-4 gm, 3-4 times daily. Therapy should be reviewed after 14 days. Not recommended for childrenSide effects: Same as Ibuprofen , but with higher incidenceSulindac:- It is a prodrug effective only after conversion to sulfide by liver enzyme.90% absorbed from git , half life of the drug is 7-8hrs, and of sulfide 18hrs, bound to plasma protein extensively Excreted in bile and then reabsorbed from intestine. The enterohepatic cycling prolongs its duration of action up to 16 hrs. 30% excreated in urine and 25% in feces.Its anti-inflammatory effect less than that of indomethacinIndication: use for pain and inflammation of rheumatoid arthritis, musculoskeletal disorders and gout, adverse effect similar to other NSAIDs, but GIT, CNS and renal side effects less than indomethacin..The dose for inflammatory arthritis = 200 mg twice daily (bid).

11. Fenamates:Mefenamic acid and meclofenamatePeak plasma level for mefenamic acid 2hrs and meclofenamate 2-4hrs , Half life for both 2-4hrs, 50% excreated in the urin.Mefenamic acid is used primarily as analgesic in rheumatoid arthritis, soft tissue injury and dysmenorrheal. Toxicity limit its usage to short –term trail Adverse effects: GIT dyspepsia and discomfort, bowel inflammation and diarrhea which may be sever. Hemolytic anemia is a serious side effect and may be of immune origin.Tolmetin Rapidly and completely absorbed from GIT , peak level: 20-60min , half life:5hs, extensively bound to plasma protein, and excreted completely in urine Indicated in the treatment of juvenile and adult rheumatoid arthritis as well as osteoarthritis.Adverse effects : as other NSAIDS :GIT, CNS, and anaphylactoid reaction

12. Enolic acid derivatives:PiroxicamAn oxicam NSAID derivative. has a prolonged duration of action which permits once daily administration. As anti-inflammatory, it is equipotent to aspirin, indomethacin and naproxan. Oral bsorption is virtually completed, peak level 3-5hrs, half life 50hrs., can be used once daily, piroxicam and its metabolites are excreted in urine.Indications: Rheumatoid arthritis Osteoarthritis, musculoskeletal disorders, ankylosing spondylitis, postoperative pain and gout.Dosage form: Capsules, suppositories.Dose: Adults: 10-20 mg PO 1-2 times/day . For acute gout, 40 mg initially, then 40 mg daily in single or divided doses for 2 days, then 20 mg / d. for 7-14 days.Child: Not to be used.Adverse effects: better tolerated than aspirin and indomethacin, cause GIT side effects in 20% of the treated patients. Tenoxicam:Similar to piroxicam, except half life 72hrs

13. Para- amino Phenolic acidsParacetamol or Acetaminophen (N-Acetyl-pamino-phenol-APAP) It is equivalent to aspirin in relieving pain and reducing fever, but it has little effect on platelet function, does not affect bleeding time and generally produces no gastric bleeding or ulcers. It has no anti-inflammatory action in usual doses because it has less effect on cyclooxygenase in peripheral tissues.Paracetamol reduces fever by direct action on the hypothalamus heat-regulating center with consequent peripheral vaso-dilatation and sweating. The drug is completely absorbed from the GI tract, less complete absorption takes place from rectal suppository. 1st pass metabolism occurs in luminal cells of the intestine and hepatocytes. Peak effect occurs within 0.5-2 h., and duration is 3-4 h. It is conjugated in the liver to form inactive glucoronide conjugates or sulphate metabolites which excreated in urin, a portion of the drug is hydroxylated to form N-acetyl benzoquineimine (NABQI). At normal dose (NABQI) react with sulfhydryl group of glutathione forming a non toxic substance. In high doses (NABQI) react with sulfhydryl groups of hepatic proteins, forming covalent bonds, hepatic necrosis and renal tubular necrosis are very serious and potentially life threatening sequellae of paracetamol posisoning.

14. Indications:Used as analgesic and antipyretic. It is a drug of choice as analgesic and to reduce fever in children. Dosage form: Tablets, capsules, suspension, suppositories .Dose: Adult: PO: 325-650 mg / 4-6 h. as needed; max. 4 g/24 hours.Adverse effects:It rarely causes any side effects. Heavy alcoholics and smokers are more susceptible to liver toxicity. Skin rashes and neutropenia are very rare. Contraindications: In patients with severe liver and kidney damage.Toxicity(overdose):With large doses, the available glutathione in the liver is depleted and NABQI reacts with sulfhydryl (SH) groups of hepatic proteins forming covalent bonds → leading to hepatic necrosis and very serious life threatening condition can result.Symptoms: Acute poisoning symptoms include nausea, vomiting, drowsiness, confusion, liver tenderness, low blood pressure, cardiac arrhythmia, jaundice and acute hepatic and renal failure.Treatment: Refer to the emergency room as soon as possible. N-acetylcysteine is a specific antidote for Paracetamol toxicity. N-acetylcysteine contain sulfhydryl groups to which toxic metabolites can be bind. Can be life saving if administered within 10 hrs of the overdose. Administration of activated charcoal will adsorb acetylcysteine, so avoid administration.

15. COX-2 Selective inhibitors: Coxibs:Celecoxib:- More selective COX-2 inhibitor than COX-1, does not inhibit platelet aggregation and does not increase bleeding time. -Used in rheumatoid arthritis and osteoarthritis-Readily absorbed from GIT , peak conc. 3hrs, t1/2 of 11 hrs, extensively metabolized in liver, excreted in urine and in feces. Abdominal pain, diarrhea, and dyspepsia are the most common side effects. The incidence of GIT ulceration was less than other NSAIDS . - contraindicated in patients with (salfomamides) allergy ( those patients used non-selective COX inhibitors with proton pump inhibitors).Etoricoxib:- High selective COX-2 inhibitor (second generation). t1/2 = 22 hrs - It is extensively metabolized by hepatic enzymes and excretion in urine.-Indicated for the treatment of osteoarthritis, gouty arthritis and relief of acute musculoskeletal pain. Rofecoxib:- Potent selective COX-2 inhibitor, used for the treatment of, asteoarthritis and rheumatoid arthritis. - it is an analgesic and antipyretic, t1/2 = 17 hrswith low effect on GIT.Valdecoxib:- highly selective COX-2 inhibitor. - t1/2 = 8-11 hrs Less GI toxicities. In treatment of dysmenorrheal pain, it is as effective as non selective NSAIDsMeloxicam:- Used orally, half life : 20 hrs. - Inhibit COX-2 more than COX-1 (especially at lower doses). - It is used for the treatment of most rheumatic diseases. - It showed less GIT symptoms & complications than piroxicam, diclofenac and naproxen.

16. Treatment of Gout:Gout associated with increased body stores of uric acid. Acute attacks involve joint inflammation caused by precipitation of uric acid crystals.Treatment strategies include:Reducing inflammation during acute attack [ Colchicine and NSADS(indomethacin or naproxen, Aspirin should not be used, since salicylates increase urate concentration)]Acceleration renal excretion of uric acid with uricosuric drugs ( probenecid and sulfinpyrazone)Reducing the conversion of purines to uric acid by inhibition of xanthine oxidase (allopurinol)Reducing inflammation during acute attackColchicineAn anti-gout agent that is not an analgesic , not a uricosuric, and will not prevent progression of gout to chronic gouty arthritis. It reduces inflammatory response to the deposited crystals and also reduce leukocyte migration and decrease phagocytosis, these effect helps reduce the incidence of acute attack. It is a good alternative to NSAIDs, and probably as effective. It is of value in patients with heart failure since unlike NSAIDs it does not induce fluid retention, also it can be given to patients receiving anticoagulants.Indications: For pain relieve of acute attacks of gout. Short term prophylaxis during initial therapy with allopurinol or uricosuric drugs. However it is also used for other purposes (amyloidosis, Behcet’s syndrome, Familial Mediterranean fever, idiopathic thrombocytopenic purpura, primary biliary cirrhosis, and various skin disorders).Doses: In gout: 1 mg PO initially, given at the first warning of an acute attack, followed by 0.5-1 mg/ 2-3 h. till relief of pain is obtained, or vomiting or diarrhea occur; max. 10 mg/day .One should wait 3 days before initiating a second course to minimize the possibility of cumulative toxicity. As prophylaxis or maintenance of recurrent gouty arthritis: 0.5-1 mg PO once or 3 times daily.Side effects: GI effects; vomiting, diarrhea, abdominal pain and nausea may occur, especially with maximum doses, and particularly troublesome in the presence of peptic ulcer or spastic colon. Bone marrow depression with aplastic anemia, agranulocytosis, myopathy, loss of hair, reversible azospermia (fertility impairment), hypersensitivity, and dermatoses have all been reported. NSADS used in gout: (indomethacin or naproxen, Aspirin should not be used, since salicylates increase urate concentration) as mention previously.

17. Acceleration renal excretion of uric acid with uricosuric drugsUricosuric drugs ( probenecid and sulfinpyrazone)These drugs are weak acids, they compete with uric acid for reabsorption in the proximal renal tubules. Chronic gout is treated with uricosuric acid and allopurinol, these drugs of no value in acute gouty attack. They have no analgesic or anti-inflammatory activity.Dose: Probenecid: To prevent gout: 0.5g/day is taken by mouth for the first week rising to 1-2g/day total. Sulfinpyrazone 100-200 mg 1-2 times a day, for 1 wk, then increase to 200-400 mg twice a day increased over 1-3 wks. It may be reduced to 200 mg after contolling of serum urate. Maximum dose is 600 mg/d. Adverse effects: Probenecid: GIT upset in few patients and occasionally allergy. It block renal tubular secretion and prolonge the effects of many drugs including penicillins, cephalosporins, acyclovir, naproxane, indomethacin, methotrexate, sulphonylureas.Sulfinpyrazone: Most frequent include: upper GI disturbances, nausea, diarrhea, blood loss, reactivation or aggravation of peptic ulcer, precipitation of acute gout attacks.

18. Reducing the conversion of purines to uric acid by xanthine oxidase  Allopurinol: Allopurinol inhibits uric acid synthesis by inhibiting xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine (end product of purine catabolism) to uric acid, so it reduces endogenous uric acid production. It is used for patients who overproduce uric acid. It has no analgesic, anti-inflammatory, or uricosuric actions, therefore, it is not useful for acute gouty attacks and may actually aggravate it. Indication:To control primary hyperuricemia that accompanies severe gout, and to prevent possibility of flare-ups of acute gouty attack.( and for other purposes: to prevent recurrent calcium oxalate stones, prophylactically to reduce severity of hyperuricemia associated with antineoplastic and radiation therapies, both of which greatly increase plasma uric acid levels in the body). Dose:Hyperuricemia: 100 mg daily initially, may be increased by 100 mg/wk; max. 800 mg daily. Serum uric acid level of ≤ 6 mg/dl should be attained.Control of gout, and secondary hyperuricemia: 200-300 mg/day for mild gout, 400-600 mg/day for moderate to severe. Initially 100 mg daily as a single dose, after food, gradually the dose is increased over 1-3 wks according to the plasma or urinaryuric acid concentration to about 300 mg. Usual maintenance dose is 200-600 mg/d.,max. 800 mg daily.Adverse effects:Drowsiness, headache, nausea, vomiting, diarrhea, abdominal discomfort, hotosensitivity, urticaria, pruritic maculopapular rash, jaundice, increased alkaline phosphatase, AST and ALT liver enzymes, hepatotoxicity, xanthine renal calculi, agranulocytosis, aplastic anemia, bone marrow depression have all been reported.

19. Opioid Pharmacology1-Opium – a mixture of alkaloids from Papaver somniferum 2-An opiate is a naturally occurring alkaloid, i.e., morphine or codeine3-An opioid is any natural or synthetic compound, which has morphine-like properties. Opioid Classification based on intrinsic activity- Agonists (morphine, fentanyl) - Pure antagonists (naloxone, naltrexone) - Mixed agonist-antagonists (pentazocin, nalbuphine, butorphanol)

20. Receptors: Mu (μ), Kappa (κ), Delta (δ) and Sigma (σ) opioid receptorsMu (μ): -found primarily in the brainstem and medial thalamus. responsible for supraspinal analgesia, respiratory depression, euphoria, sedation, decreased gastrointestinal motility, and physical dependence. Subtypes include Mu1 and Mu2, Mu1 related to analgesia, euphoria, and serenity, Mu2 is related to respiratory depression, pruritus, prolactin release, dependence, anorexia, and sedation. Kappa (κ): -found in the limbic and other diencephalic areas, brain stem, and spinal cord responsible for spinal analgesia, miosis, sedation, dyspnea, dependence, dysphoria, and respiratory depression. Delta (δ): dysphoria, and stress-induced depression. located largely in the brain responsible for psychomimetic and dysphoric effects. Sigma (σ): responsible for psychomimetic effects, They are no longer considered opioid receptors

21. Endogenous Opioid Peptides1. Enkephalins Relatively selective Delta (δ) receptors.-Widely distributed in CNS; - Act like morphine to modulate neurotransmitter release.- Found with catecholamines in sympathetic terminals and adrenal.2. Endorphins It binds preferentially to μ receptors; Localized primarily in pituitary and hypothalamus.3. Dynorphins a potent and highly selective agonist at κ receptors; - Similar distribution to the enkephalins.- Opioid peptides function as neurotransmitters or neuromodulators.- Modulate pain transmission in the cord and alter acetylcholine release in the myenteric plexus.- Play fundamental roles in hormonal secretion, thermoregulation, and cardiovascular control.

22. Opioid Agonists – PharmacodynamicsThe opioid-like peptides inhibit synaptic transmission by binding to opioid receptors on the presynaptic membrane and the post-synaptic membrane of the synapse. On the pre-synaptic membrane they inhibit the opening of the calcium channels and so prevent the release of the neurotransmitter that sends the signal to the receiving neuron. On the post-synaptic membrane, the opioid-like peptides bind to opiate receptors and make the membrane less responsive to stimulation by neurotransmitters. Morphine and other opioid drugs are similar in molecular structure to the opioid-like peptides so they bind to the same opioid receptors and produce the same effect – inhibition of the pain transmission across the synapseGeneral Clinical Properties:Acute: Analgesia; Miosis; Respiratory Depression; Nausea and vomiting; Sedation; Skeletal muscle hypertonus; Euphoria; Constipation; Vasodilatation; Urinary retention; Bradycardia; Biliary Spasm; Cough suppressionChronic: Tolerance; Physical Dependence- All of the clinically-used μ opioid agonists produce these effects.- The few qualitative differences between drugs (e.g. histamine release) usually do not involve specific opioid receptor mechanisms.- Opioids differ greatly in physicochemical properties as well as speed of onset and duration of action, so clinical selection is frequently based on pharmacokinetic considerations.

23. Mechanisms:a. Analgesia and Mood Processing of pain information is inhibited by a direct spinal effect at the dorsal horn. Probably involves presynaptic inhibition of the release of tachykinins like substance P. Rostrad transmission of pain signals decreased by activation of descending inhibitory pathways in the brainstem. Emotional response to pain altered by opioid actions on the limbic cortex. Opioids may act at receptors located peripherally on sensory neurons. Possibly important in painful conditions accompanied by tissue inflammation.Clinical characteristics: Selective relief of pain at doses which do not produce hypnosis or impair sensation. Typically, patients report that pain is still present, but the intensity is decreased and it no longer bothers them as much. Mood elevation, sometimes frank euphoria can occur. Sense of well-being and cloudy detachment thought to be an important reason for opioid abuse. Some types of pain more responsive to opioids than others. More effect in prolonged, burning pain than sharp pain of an incision. Neuropathic pain (e.g. pain of nerve root compression) can be very resistant.b. Sedation-Hypnosis- Drowsiness, feelings of heaviness, and difficulty concentrating are common. - Sleep may occur with relief of pain, although these drugs are not hypnotics. Most likely to occur in elderly or debilitated patients and in those taking other CNS depressants (EtOH, benzodiazepines).c. CNS Toxicity- Dysphoria and agitation occur infrequently (incidence higher with meperidine and codeine). - Seizures can be produced by meperidine—major metabolite, normeperidine, is a convulsant. - Opioids generally avoided in head injury or when elevated intracranial pressure (ICP) is suspected. 1. ↓ ventilation can ↑ PaCO2 and raise ICP further.2. Pupil effects may mask changing neurologic signs.

24. d. Respiratory DepressionMechanism: - Direct effects on respiratory centers in the medulla. - Dose-related depression of ventilatory response to hypercarbia and hypoxia. This shifts CO2 response curve to the right. - May involve a distinct subset of μ2 receptors.Clinical Characteristics: With usual analgesic doses, arterial O2 saturation often decreases. Drive to breathe may be abnormal despite an apparently normal respiratory rate and state of consciousness. Effects are dose related. First CO2 and hypoxic response are depressed, then respiratory rate slows. Very large doses may cause irregular or periodic breathing and eventually apnea. Trouble most likely to occur with pre-existing pathology (such as hypothyroidism, pulmonary or CNS disease) or previous drug administration (alcohol, general anesthetics, benzodiazepines). Sleep depresses the response to CO2 and potentiates the opioid effect.Respiratory depression is the major toxicity of opioids and nearly always the cause of death from overdose. Equi-analgesic doses of all opioids produce equivalent amounts of respiratory depression. There is no convincing evidence than any analgesic is more or less dangerous than morphine in this regard.Both analgesia and respiratory depression are reduced by administration of an opioid antagonist or by the development of tolerance. important clinical implications: 1. Tolerant individuals who require large amounts of opioid for relief of pain are not at proportionately increased risk for respiratory depression 2. Respiratory depression is difficult to reverse without reversing some analgesia.

25. d-Cough suppression:Depression of cough centers in the medulla (and possibly, the periphery). Different molecular mechanism than analgesia or respiratory depression— cough suppressed by dextro-isomers of opioids (e.g. dextromethorphan), compounds which have no analgesic activity.  e- Pupillary Constriction:  Stimulation of Edinger-Westphal (parasympathetic) nucleus of the oculomotor nerve to produce miosis. Pinpoint pupil is a pathognomonic sign of opioid overdose. Antagonized by naloxone, atropine or ganglionic blockers.  f-Nausea and vomiting: Direct stimulation of the chemoreceptor trigger zone (CTZ) in the area postrema on the floor of the fourth ventricle. This activates the vomiting center proper Emetic effects markedly potentiated by stimulation of the vestibular apparatus, so ambulatory patients are much more likely to vomit than those lying quietly.- In animals (and man?), very high doses can depress the vomiting center

26. g-Muscle Rigidity- Large i.v. doses can cause generalized stiffness of skeletal muscle. Thought due to μ-mediated increase in striatal dopamine synthesis and inhibition of striatal GABA release.- Most common with fentanyl and congeners.- May play a role in some overdose fatalities.4- Cardiovascular effects: Decrease in central sympathetic tone causes vasodilation and orthostatic hypotension. Effects on both capacitance and resistance vessels. Bradycardia by stimulating central vagal nuclei Little or no myocardial depression.5- Histamine release: Morphine, codeine, meperidine cause non-immunologic displacement of histamine from tissue mast cells. Occasionally redness, hives, itching near injection site. Rarely, hypotension, generalized flushing. Not an allergy—true allergic responses to opioids are very rare. Facial itching and warmth are common after opioids—probably a dysesthesia which has nothing to do with histamine.

27. 6- Smooth muscle effect:a. Intestine and Stomach- Spasm of smooth muscle all along the GI tract. Both small and large bowel become hypertonic, but rhythmic propulsive activity is diminished. Delay in intestinal transit time and spasm of the anal sphincter cause constipation.- Delayed gastric emptying. Important because it may slow absorption of oral medications.- Mechanism involves both CNS effects and peripheral actions on opioid receptors in the enteric plexus. Smooth muscle effects of morphine > meperidine > agonist-antagonist opioids. Chronic administration of opioids frequently necessitates the administration of laxatives and stool softeners to treat constipation. Recent evidence that poorly-absorbed quaternary opioid antagonists are also effective in reversing this local effect. Constipating effect is used therapeutically for treatment of diarrhea. Diphenoxylate (in Lomotil) and loperamide (Imodium) are poorly-absorbed opioids that do not produce central effects. b. Biliary System - Contraction of smooth muscle along the biliary tree and spasm of the sphincter of Oddi. - Can precipitate biliary colic on rare occasions. - Effect antagonized by naloxone and partially reversed by glucagon, nitroglycerin, or atropine. c. Urinary Tract - Increase contractions of the ureter and tone of the urinary sphincter, but decrease force of detrusor muscle contraction. Decreased attention to full bladder. Can cause urinary retention. - Probably both central and peripheral mechanisms involved. 7. Effects on Pregnancy and the Neonate - All cross the placenta. No teratogenic effects, but chronic use may cause physical dependence in utero. Neonatal withdrawal after delivery can be life-threatening. Opioids given during labor can cause respiratory depression in baby.

28. 8. Tolerance -Reduction in effect with repeated dosing (or higher dose to produce same effect). First indication usually decreased duration of analgesia, then decreased intensity. - Cross-tolerance to other opioids. - Mechanism not known precisely. Involves adaptive response of adenylyl cyclase and/or G protein coupling. Not a pharmacokinetic effect. -Develops most rapidly to depressant effects like analgesia, respiratory depression, euphoria, but much less tolerance to stimulatory effects like constipation or miosis. This has some important clinical consequences:1. Heroin addicts or methadone maintenance patients may have little euphoria from high doses but continue to experience constipation and miosis. 2. Terminal cancer patients and others requiring high doses for analgesia are also tolerant to respiratory depression (cf. p. 6), but they frequently require treatment for constipation. 9. Physical Dependence -Adaptation which produces stereotyped withdrawal syndrome (abstinence) when drug is stopped. Symptoms stop when small dose of opioid is given. - Giving antagonist (naloxone) to physically dependent person causes rapid onset of more severe precipitated abstinence. - Withdrawal symptoms include runny nose, vomiting, diarrhea, gooseflesh, mydriasis, shaking chills, drug seeking behavior. - Physical dependence not the same as psychological dependence or addiction. Mild physical dependence may be common.

29. Opioids agonists:1-Morphine and related opioids:Morphine:Morphine is the standard opioid to which others are compared and remains a valuable drug for the treatment of acute, severe pain. Rapid absorption from GIT, wide distribution, The analgesic effect is greater when the drug is administered IM or IV compare with oral route and rapid clearance from plasma. Peak effect after IV bolus is 15 min. Duration of action is between 2 and 3 h. Both liver and kidney function are responsible for morphine elimination. The liver mainly metabolizes it. One of the principal metabolites morphine-6-glucuronide, it is also a potent opioid agonist and may accumulate and induced toxicity ( opioids depression) in renal failure. Polar metabolites cleared by kidney.Effects: Analgesia, vomiting, respiratory depression, miosis,, orthostatic hypotension (vasomotor medullary depression), Constipation (↓ peristalsis), ↓ pancreatic and biliary secretion, constrict the sphincter of Oddi (↑biliary pressure), ↑ detrusor muscle tone ( → felling of urgency), bronchospasm (↑ histamine release and vagal stimulation) and pruritis (↑ histamine release) Uses : Relief of severe pain ( MI, terminal illness, surgery, obstetric procediures), To facilitate mechanical ventilation, acute left ventricular failure- by relieving anxiety and producing vasodilatationContraindications: Airway obstruction and pain caused by biliary colicAdministrationIV bolus: 2.5 mg every 15 min as required, IV infusion rate: 1–5 mg/h dilute in 5% glucose or 0.9% saline Adverse effects: Respiratory depression and apnoea, hypotension and tachycardia, nausea and vomiting, delayed gastric emptying, reduce intestinal mobility, biliary spasm, constipation, urinary retention, histamine release, tolerance, pulmonary oedema. 

30. Codeine It can be taken from opium or synthesized by methylation of morphine. Codeine has a low affinity for the µ and k opioid receptors, 1/20 of the analgesic activity of morphine. It has a high oral/ parenteral potency ratio so when given orally , it is 60% as potent as when injected IM. It is useful as an antitussive and for the treatment of diarrhoea. side-effects. Respiratory depression is seldom a problem. This explains its traditional use to provide analgesia for head-injured and neurosurgical patients. Doses: 60 mg , of it 10% undergoes demethylation to morphine – this possibly contributing to the analgesic effect.Uses : Mild to moderate pain, Diarrhoea and excessive ileostomy output and Antitussive. Codeine has antitussive effects, is especially useful in relieving painful cough. It also exerts a drying action on the respiratory mucosa that may be useful (e.g., in bronchorrhea). At doses used for cough suppression, codeine has minimal respiratory depressant effects. Nausea, vomiting, constipation, tolerance to antitussive as well as analgesic effects, and physical dependence can occur, but potential for abuse is low. Contraindications: Airway obstructionAdministration: Orally 30–60 mg 4–6 hourly (the analgesic effect of 30 mg codeine orally= 600 mg aspirin), IM 30–60 mg 4–6 hourlyAdverse effects: drowsiness, constipation, nausea and vomiting and respiratory depression (less GIT side effects and respiratory depression than morphine). Less addiction liability and less withdrawal than morphineCausions: Enhanced sedative and respiratory depression from interaction with: benzodiazepines, Antidepressants, anti-psychotics, MAOI (hypertension, hyperpyrexia, convulsions and coma), Head injury and neurosurgical patients (may exacerbate ↑ ICP as a result of ↑ PaCO2).Heroin:It is diacetylated morphine, with more rapid onset and shorter duration than morphine, but with greater analgesic effect 3 mg heroin= 10 mg morphine, a drug of abuse and not used clinically.

31. 2-Meperidine and related congeners: Meperidine:Synthetic opiods, as analgesic it is 1/8 as potent as morphine(100 mg meperidine= 15 mg morphine).Rapid absorption by all rotes and it is better absorbed orally, wide distribution, and rapid clearance from plasma. Clearance mainly by hepatic biotransformation (48-56% first pass). Metabolized by N-demethylation to normeperidine, oxidation to meperidinic acid or normeperidinic acid. Normeperidine is a CNS stimulant and can produce convulsions in man.Metabolite has T½ of 8-12 hr so significant amounts may accumulate. Metabolites excreted in urine. Toxicity most likely with high doses in renal failure. Cause histsamine release and broncospasm, cause respiratory depression and possess addiction liability, withdrawal effects less severe than morphine. Possess weak atropine like activity cause medriasis, has no GIT and antitussive activity. In IV injection , toxicity increased. Repeated IM injection causes tissue irritation.

32. Fentanyl Congener of meperidine, 80 times the analgesic and the respiratory suppressant effect of morphine, when combined with droperidol , it causes dissociative anesthesia, its principle use in anesthesia Rapid absorption, wide distribution, moderately rapid hepatic clearance, More than 60% first-pass metabolism to inactive metabolites. Extremely lipophilic. Rapidly crosses BBB and other membrane barriers so effects parallel changes in plasma concentrations (rapid onset, within 1–2 min after IV injection and a peak effect within 4–5 min, duration of action after a single bolus is 20 min.). More effective than morphine in maintaining hemodynamic stability. High dose caused muscle rigidity.Dose: For sedation: IV infusion: 1–5 microgram/kg/h , During anaesthesia IV bolus: 1–3 microgram/kg with spontaneous ventilation, 5–10 microgram/kg with intermittent positive pressure ventilation, Up to 100 microgram/kg for cardiac surgeryAdverse effects: Respiratory depression and apnoea, Bradycardia and hypotension, Nausea and vomiting, Delayed gastric emptying, Reduce intestinal mobility, Biliary spasm, Constipation, Urinary retention, Chest wall rigidity (may interfere with ventilation), Muscular rigidity and hypotension more common after high dosage

33. AlfentanilSynthetic opioids, with more rapid onset. It is 30 times more potent than morphine and its duration is shorter than that of fentanyl. The maximum effect occurs about 1 min after IV injection. Duration of action following an IV bolus is between 5 and 10 min. Its distribution volume and lipophilicity are lower than fentanyl. It is ideal for infusion and may be the agent of choice in renal failure. The context sensitive half-life may be prolonged following IV infusion. In patients with hepatic failure the elimination half-life may be markedly increased and a prolonged duration of action may be seen. Uses: Patients receiving short-term ventilation; Contraindications: Airway obstruction and Concomitant use of MAOI. Administration : IV bolus: 500 mcg every 10 min as necessary, IV infusion rate: 1–5 mg/h (up to 1 mcg/kg/min). Don’t use alfentanil: In combination with an opioid partial agonist, e.g. buprenorphine (antagonizes opioid effects). Adverse effects: Respiratory depression and apnoea, Bradycardia, Nausea and vomiting, Delayed gastric emptying, Reduce intestinal mobility, Biliary spasm, Constipation, Urinary retention, Chest wall rigidity (may interfere with ventilation)Diphenoxylate:It is derivative of meperidine, it causes few morphine subjective effects, has no addiction laiability. Mainly use for treatment of diarrhea, combined with atropine (Lomotil, Entrostop)

34. 3-Methadone related congeners:Methadone:It is synthetic diphenylheptane. It has very similar actions to morphine, but more effective orally,it is less sedating and longer acting. Its main use is by mouth to replace morphine heroin or diamorphine when these drugs are being with-rawn in the treatment of drug dependence. The duration of analgesic of methadone is equal to that of morphine although the half life is much more which can be resulted in accumulated toxicity. Well absorbed orally , metabolized in liver and excreted in urine and bile. Methadone given once daily under supervision is preferable to leaving addicts. The object is to reduce craving for opioids and minimize withdrawal effects by occupying opioid receptors. Methadone is also becoming more widely used in the treatment of chronic or terminal pain. Adverse effect the same as morphine, both tolerance and physical dependence Propoxyphene: It is structural analogue of methadone, with a spectrum of activity (especially analgesia) similar to that of codeine.prepared as water soluble hydrochloride, it is absorbed rapidly, metabolized to N- demethylated metabolites which slowly excreted in urine. Abuse comparable to that of codeine, Physical dependence and tolerance occurs when used in high doses for long period.

35. 4- Non opioids antitussive:Dextromethorphan:A congener of the narcotic analgesic levorphanol, has no significant analgesic or sedative properties, does not depress respiration in usual doses, and is nonaddictive. No evidence of tolerance has been found during long-term use. Extremely high doses may depress respiration.

36. Opioid Agonist-Antagonists1. Developed in search for less abusable potent analgesics.2. All have analgesic (agonist) properties as well as ability to antagonize morphine effects 3. Two basic mechanisms:- Partial agonists at μ receptor. Buprenorphine has high affinity, but limited efficacy at μ receptor. Given alone, it has morphine-like effects. Competes effectively with agonists like morphine and may reduce effect.- Agonists/Partial agonists at κ receptor. Nalorphine, pentazocine, nalbuphine, butorphanol act as κ agonists (probably κ3) to produce analgesia. Also act as competitive antagonists at μ receptors (high affinity but no efficacy at this receptor).4. Clinical properties: -Potent analgesics effective in moderate to severe pain.-Relatively limited toxicity (respiratory dep., smooth muscle) -Decreased abuse potential, but also decreased patient acceptance (mood elevation may be clinically important!). -Occasional dysphoria or hallucination with κ agonists -Antagonist properties mean they can precipitate withdrawal in patients already receiving chronic treatment with opioid agonists.5. Neither agonist vs. antagonist potency nor μ/κ selectivity seem to predict clinical utility or patient acceptance. 

37. Opioid Antagonists1. Naloxone - Pure, competitive antagonist at μ, κ, and δ receptors (highest affinity at μ). Given alone, almost no effect. Some behavioral effects in animals. - Rapidly reverses opioid overdose, but effect short due to redistribution.Patient may become renarcotized.2. Naltrexone -Used orally in high doses to treat detoxified heroin addicts (blocks euphoriafrom injected heroin). -Effects primarily from active metabolite, 6-β-naltrexol.