Chapter 19 Narcotic Analgesics: I General Consideration

CHAPTER 19 Narcotic Analgesics I General Consideration 【 action mechanism 】 ligands → opioids receptor → inhibitory G proteins → inhibiting adenylate cyclase,or increasing potassium ion efflux or reducing calcium ion influx → impeding neuronal firing and transmitter release.

1.Ligands (1)endogenous: endorphins from pituitary β-endorphin dynorphin enkephalins from brain M-enkephalin L-enkephalin (2)exogenous: drugs 2.Receptor (1)class of opioid receptors: μ, κ, σandδ. (2)location of opioid receptors: CNS, nerve terminals in periphery, cells of gastrointestinal tract. 3.analgesic properties of opioids are primarily mediated by μ,κreceptor.

【 characteristics 】 relieving pain without affecting other senses and consciousness. high potency of analgesia. addiction. 【 clinical use 】 intense pain and the anxiety that accompanies it.

【 classification of drug 】 1. natural opiates: morphine, heroin, codeine, thebaine, paraverine. synthetic analgesics: meperidine, methadone, fentanyl, anadol, etorphine, pentazocine. 2. strong agonist: morphine, heroin, meperidine, methadone, fentanyl moderate agonist: codeine, propoxyphene. mixed agonist-antaginist: buprenorphine,pentazocine. antagonist: naloxone,naltrexone

Ⅱ Natural Opiates Morphine 【 mechanism of action 】 Morphine activates opiate receptor to produce analgesic effect like endogenous opiate peptides.

high affinity for μ receptors,varying affinities forδandκreceptors,and low affinity for σ receptors in CNS and gastrointestinal tract.*

Sensory neuron

second neuron

sp

sp sp

E E Enkephalin Neuron

sp=substences P E=enkephalin

【 pharmacokinetics 】 1.goodl absorption from gastrointestinal tract, but significant first-pass effect. Subcutaneous injection is commonly used. 2.rapidly entering to all body tissues,including fetuses of pregnant women.not used for analgesia during labor. Duration of action is 4 to 6 h.

【 pharmacologic effects 】 1. effects on CNS (1) analgesia and sedation: prominent effect. characteristics: strong analgesia. effective on various pains: chronic dull pain,colic and acute sharp pain. no effect on other senses and consciousness. sedation: relieving anxiety, stress accompanied with severe pain. analgesia with euphoria in partial patients. (2) emesis by direct stimulation of CTZ to cause nausea and vomiting.

(3) respiratory depression by reducing responsiveness of respiratory centers in brain stems to blood level of CO2. (4) suppression of cough by direct inhibition of cough center. (5) miosis by stimulating Edinger-Wesphal nucleus, pinpoint pupils are indicative of toxic dosage. 2.cardiovascular effects (1)peripheral vasodilation to cause orthostatic hypotension inhibition of vasomotor center. promotion of release of histamine from mast cells. (2)cerebral vasodilation to increase intracranial pressure: depression of respiration and increasing blood CO2.

3. gastrointestinal effects (1)relieves diarrhea or causes constipation reducing peristalsis and stomach mobility increasing spasmodic nonpropulsive contraction decreasing biliary and pancreatic secretions to cause indigestion. (2)increasing biliary pressure by constriction of Oddi's sphincter to induce biliary colic. 4.other effects bronchoconstriction by histamine. retention of urine by increasing sphincter tone of bladder.

【 therapeutic uses 】 1. analgesia. acute sharp pain(intense pain). anginal pectoris by analgesic, sedative and vasodilative effects. biliary and kidney colic etc., combined with atropine. 2. acute pulmonary edema vasodilation which results in the decrease of peripheral resistance and increase of the capacity of peripheral vessels. 3. severe diarrhea.

【 adverse effects 】 1.common side effects ： nausea, vomiting, constipation, biliary colic, respiratory depression, dysphoria, hypotension,acute urine retention. 2.tolerance and physical dependence ： withdrawal symptoms ： autonomic,motor and psychological responses （ insomania, dysphoria, headache, sweating, vomiting, diarrhea, tremor, collapse ） .

【 Contraindication 】 1.women in delivery and lactation. 2.patients with bronchial asthma and pulmonary heart disease. 3.patients with cranial injury and high cranial pressure.

Codeine 1.codeine is the 3-methyl ether of morphine. 2.pharmacologic effects are similar to morphine, but its analgesic potency is 1/12 of morphine, cough depressant potency is 1/4 of morphine. 3.analgesic effect is strongr than aspirin. 30mg of codeine is equivalent to 600mg of aspirin. 4.less sedation, respiratory depression and fewer gastrointestinal effects. 5.use: mild to moderate pains and severe cough by oral administration. 6.physical dependence in long-term administration.

Ⅲ Synthetic Analgesics Pethidine(Meperidine,Dolantin) 1.activating opioid receptors,particularlyκreceptors. 2.pharmacologic effects are similar to morphine, but less potency and shorter duration in analgesis, sedative and respiratory depression. no effect on cough, bronchial and gastrointestinal smooth muscles. 3.use: replacing morphine to relieve intense pains and to treat acute pulmonary edema, and to induce artificial hibernation.not useful for diarrhea or cough. 4.mild adverse effects similar to morphine 5.tolerance: being cross with the other opioids. dependence: in long-term use.

Methadone 1.analgesic effect is equal to morphine in potency and duration of action, but more effective in oral administration than morphine. 2.use: analgesia, suppression of withdrawal syndrome ,treatment of heroin user.Orally administered, methadone is substituted for injected opioids and patient is then slowly weaned from methadone. 3.physical dependence occurs slowly and withdrawal syndrome is mild.

Fentanyl 1.analgesic effect is 80-100 times as effective as morphine with short duration(15 to 30 min) and rapid onset. 2.use: anesthesia or anesthesic adjunct. Alfentanil Alfentanil has a more rapid onset of action and shorter duration of narcotic effect than fentanyl. It is used as an adjunct to general anesthetics and as an anesthetic inducing agent.

Ⅳ Opioid Receptor Antagonists 1.partial antagonists: precipitate a withdrawal syndrome in opioid addicts. (nalorphine, pentazocine, butorphanol, nalbuphine, buprenorphine). 2. full antagonists: naloxone and naltrexone. naloxone may reverse the acute poisoning effects of opioid agonists and precipitate a withdrawal syndrome in opioid addicts.

CHAPTER 20 Central Stimulants 【 Classification of drug 】 1. cerebral stimulants: caffeine. 2. respiratory stimulants: nikethamide, lobeline. 3. spinal cord stimulants: strychnine.

I Cerebral Stimulants Caffeine 【 action mechanism 】 caffeine→ blocking adenosine receptors, inhibiting PDE → breakdown of cAMP↓ → central actions and some of peripheral actions.

【 pharmacologic effects 】 1.CNS: small dose stimulating cerebral cortex vigorous loss of sleepiness medullary bulb respiratory--- hyperpnea vasomotor centers--- BP increase large dose spinal cord---convulsion

2.cardiovascular system (1)direct effects: cardiac excitement and vascular dilation. (2)indirect effects: cardiac inhibition and vascular contriction by stimulating vasomotor center and vagal center. In overall, little changes in heart rate and blood pressure in normal cardiovascular state,increasing heart rate and blood pressure in cardiovascular hypofunction. 3.other systems: relaxing bronchial smooth muscle, diuretic effect and stimulating secretion of gastric acid.

【 therapeutic uses 】 1. central inhibition 2.headache in combination with aspirin,migraine in combination with ergotamine. 【 adverse effects 】 CNS excitement: insomnia, agitation, convulsion etc..

II Respiratory Stimulants Nikethamide(coramine) 1.stimulating respiration: short and modest effect. direct stimulation of respiratory center reflex-mediated stimulation of respiratory center by stimulating chemoreceptor in carotid body increasing sensitivity of respiratory center to CO2 2.use: entral respiratory depression, no effective for peripheral respiratory depression. 3. wide margin of safety. tachcardia and blood pressure increase in the large dose.

Lobeline 1.stimulating respiratory center by stimulation of chemoreceptors in carotid and aortic bodies. 2.short effect and wide margin of safety.hardly producing convulsion in large dose. 3.use: asphyxia in the newborn CO toxication respiratory failure caused by infectious diseases in children.

CHAPTER 21 Antipyretic Analgesic and Antiinflammatory Drugs • • • • • • •

I General Consideration Inflammation is a protective response to tissue injury. Inflammation is triggered by the release of chemical mediators from injured tissues and migrating cells. Specific chemical mediators include histamine,5-HT,PGs, brandykinin,interleukin-1. nonsteroidal anti-inflammatory drugs(NSAID) or non-narcotic analgesics. Effect: antipyretic,analgesic and anti-inflamatory activities. Differences: they all exert antipyretic and analgesic actions,most also produce antiinflammatory action. Mechanisms of actions: reduction of PG biosynthesis by inhibition of cyclooxygenase.

Phospholipids ↓ PLA2 AA ↓cyclooxygenase (-) PGG2/PGH2↓ ↓ PGs↓ (PGD1, PGD2, PGE1, PGE2, PGFα, PGI2 etc.)

1. antipyretic effects: Effect: reduction of body temperature of patients with fever, no effect on normal body temperature. Mechanism: reduction of PGs biosynthesis via inhibition of cyclooxygenase to lower body temperature in patients with fever. * Use: high fever. Differences: Phenothiazides decrease both normal and high body temperature by direct inhibition of temperature-regulating center in CNS. Antipyretics decreases only high body temperature by the inhibition of PGs biosynthesis and has no effect on normal body temperature.

pathogens or toxins ↓(+) PMNs ↓ pyrogen release ↓(+) hypothalamus ↓ PG E2 synthesis and release ↓(+) body temperature-regulating center in hypothalamus ↓ set point for body temperature↑ ↓ heat production↑and heat dissipation↓ ↓ body temperature↑(fever)

1. antipyretic effects: Effect: reduction of body temperature of patients with fever, no effect on normal body temperature. Mechanism: reduction of PGs biosynthesis via inhibition of cyclooxygenase to lower body temperature in patients with fever. Use: high fever. Differences: Phenothiazides decrease both normal and high body temperature by direct inhibition of temperature-regulating center in CNS. Antipyretics decreases only high body temperature by the inhibition of PGs biosynthesis and has no effect on normal body temperature.

2. analgesic effect Effect: weak, effective on mild to moderate dull pain, little effect on colicky pain and sharp pain(intense pain). no narcotic. Mechanism: relieving pain via inhibition of PGs biosynthesis.* Use: common dull pains, e.g. headache, toothache, neuralgia, muscular pain, arthralgia and dysmenorrhea etc. Differences: narcotic analgesics--- strong analgesic effect, action site is on CNS ,activation of the opioid receptors, mainly used for sharp pain. non-narcotic analgesics--- weak analgesic effect, action site is on peripheral tissue, inhibition of PGs biosynthesis, mainly used for dull pain.

injured or inflammatory tissue PGs release

autocoid release (+) (e.g.bradykinin) (+) (+) pain receptors pain

2. analgesic effect Effect: weak, effective on mild to moderate dull pain, little effect on colicky pain and sharp pain(intense pain). no narcotic. Mechanism: relieving pain via inhibition of PGs biosynthesis. Use: common dull pains, e.g. headache, toothache, neuralgia, muscular pain, arthralgia and dysmenorrhea etc. Differences: narcotic analgesics--- strong analgesic effect, action site is on CNS ,activation of the opioid receptors, mainly used for sharp pain. non-narcotic analgesics--- weak analgesic effect, action site is on peripheral tissue, inhibition of PGs biosynthesis, mainly used for dull pain.

3. antiinflammatory effect Effect: relieving inflammatory pain and swelling. Mechanism: inhibition of PG synthesis.* Use: rheumatic and rheumatoid arthritis etc.. Differences: NSAID---weak SAID---strong

prostaglandins vasodilation

autocoids release histamine serotonin kinin increased vascular permeability edema pain, swelling

【 classification 】 1. salicylates: aspirin. 2. aminophenol derivatives: acetaminophen. 3. pyrazolon: phenylbutazone. 4. other organic acids: indomethacin etc.

Ⅱ Salicylates Acetylsalicylic acid (ASA, aspirin) 【 pharmacokinetics 】 Aspirin is metabolized in liver by the hydrolyzation to salicylate and acetic acid by esterases . Aspirin in oral small dose is metabolized in first-order kinetics and half life is 3.5 h, in the large dose (1g/time,>4g/day) it is metabolized in the zero-order kinetics because hepatic metablic pathway becomes saturated, which prolong t1/2 of aspirin to 15 h or more to lead to toxication.

【 pharmacologic effects 】 Aspirin is rapidly deacetylated by esterases in body,producing salicylate which has anti-inflammatory,analgesic,and antipyretic effects.Aspirin irreversibly acetylates cyclooxygenase to inhibit the enzyme activity. 1. antipyretic action: rapid and moderate effect. 2. analgesic effects: effective for low-to moderateintensity dull pains. 3. antiinflammatory effects: to treat rheumatoid and rheumatic arthritis, symptomatic relief. 4.antiplatelet effects: inhibits platelet aggregation and secondary release of ADP from activated platelets by inhibition of TXA2 production.*

5.other effects: increasing alveolar ventilation; increasing gastric acid secretion and diminishing mucus protection to cause epigastric distress,ulceration,and hemorrhage; resulting in retention of sodium and water to cause edema and hyperkalemia.

【 therapeutic uses 】 1. Hyperpyrexia: modest dose. 2.dull pain: e.g. headache, arthritis, dysmenorrhea etc. modest dose. 3.rheumatic fever and rheumatoid arthritis (first-line drugs) in relatively large dose. 4. prevention of thromboembolism, stroke, myocardial infarction in small dose.decreasing incidence of trnsient ischemic attack and unstable angina as well as that of coronary artery thrombosis.* 5.chronic use of aspirin reduces incidence of colorectal cancer.

【 adverse effects 】 1.Gastrointestinal reaction: epigastric distress, nausea and vomiting, gastric ulceration and bleeding. taking aspirin with meal or with sodium bicarbonate, taking enteric- coated aspirin. 2. Hepatic damage: mild and reversible. 3. prolonging bleeding time due to inhibition of platelet functions in small dose and reduction of plasma prothrombin level in large dose. 4.Large dose of aspirin uncouples oxidative phosphorylation.Energy normally used for production of ATP is dissipated as heat,which explains hyperthermia caused by salicylates when taken in toxic quantities. 5.Hypersensitivity or allergy.

6.Reye’s syndrome:Aspirin given during viral infections has been associated with an increased incidence of Reye’esyndrome(fatal,fulminating hepatitis with cerebral edema).This is especially encountered in children,who therefore should be given acetaminophen instead of aspirin when such medication is required. 7.Salicylate intoxication (salicylism): headache, mental confusion, drowsiness, difficulty in hearing, vomiting in mild toxication; and hyperventilation, severe CNS disturbulance ,respiration depression and marked alteration in acid-base balance in severe toxication. Medication: discontinuation of salicylates, gastric lavage, relieving symptoms, intravenous infusion of NaHCO3 and dialysis.

Ⅲ Aminophenol Derivatives Acetaminophen Acetaminophen inhibits prostaglandin synthesis in CNS,but less effect on peripheral cyclooxygenase. Antipyretic and analgesic similar to aspirin in potency,no antiinflammatory activity. Use: dull pain and hyperpyrexia., choice for children with viral infections or chicken pox. Adverse effects: skin rash and drug fever (allergic reaction), hypoglycemic coma, renal tubular necrosis and renal failure in long-term administration, acute hepatic necrosis in large dose.

Ⅳ Pyrazolon Phenylbutazone 【 pharmacokinetics 】 high binding rate with plasma proteins ( 98%). So, phenylbutazone may replace oral anticoagulants, oral hypoglycemic drugs, sulfonamides etc.to increase their blood level when they are administered together. inducing hepatomicrosome enzymes and disturbs metabolism of other drugs.

【 pharmacologic effects 】 powerful antiinflammatory actions, less analgesic and antipyretic effects. 【 therapeutic uses 】 chiefly in short-term therapy of acute gout ,and in acute rheumatoid arthritis and osteoarthritis and ankylosing spondylitis when other NSAIS agents have failed.The usefulness of phenylbutazone is limited by its toxicity. 【 adverse effects 】 poor toleration. common adverse effects: gastrointestinal effectsr, salt and water retention. other effects have skin rash, thrombocytopenia and granulocytopenia, agranulocytosis or aplastic anemia. Hepatic and renal injury have been reported.

Ⅴ Other Organic Acids Indomethacin 【 pharmacologic effects 】 anti-inflammatory,analgesic and antipyretic effects. more potent than aspirin as an anti-inflammatory agent,but it is inferior to the salisylates at dose tolerated by patients with rheumatoid arthritic. 【 therapeutic uses 】 Indomethacin is not routinely used for analgesia and antipyresis because of its toxicity and side effects.

【 adverse effects 】 35-50% of patients report some adverse effects and most adverse effects are dose-related. 1. Gastrointestinal complains. 2. CNS effects: frontal headache, dizziness, vertigo, mental confusion etc. 3. Hematologic effects: neutropenia, thrombocytopenia, inpaired platelet functions,rare aplastic anemia. 4. contraindication: in pregnancy or nursing women, patients with psychiatric disorders, epilepsy, parkinsonism, renal diseases, peptic ulcers and machine operators.

Ibuprofen • anti-inflammatory,analgesic and antipyretic activity. • chronic treatment of rheumatoid and osteoarthritis. • less intense of gastrointestinal effects than that of aspirin.

Other drugs • • • • • • • •

Sulindac fenamates (mefenamic acid, meclofenamate) tolmetin propionicacid derivatives (naproxen, fenoprofen, ketoprofen, flurbiprofen) piroxicam nabumetone etodolac, diclofenac, ketorolac in single agent or in the compound preparations.