General Anesthesia & Pain Mgt Drugs.pptx

This document is contain pharmacology of anesthesia

1. II. General Anesthesia: Anesthesia involves a loss of memory and awareness, and insensitivity to painful stimuli, Renders patients analgesic, amnesic, and unconscious, Provides muscle relaxation and Suppression of undesirable reflexes It has three components: hypnosis, analgesia, and muscle relaxation. Ideal properties of General anesthetics: Rapid loss of consciousness A level of analgesia sufficient to abolish the reflex reactions to pain Minimal and reversible influence on vital physiological functions 10/3/2025 1

2. Relaxation of skeletal muscle Lack of operating room safety hazards; and Prompt patient recovery to psychomotor competencey Note: None of the anesthetic drugs possesses all of the features required for ideal anesthetic management. Thus, several different drugs are usually combined to produce desired levels (Balanced anesthesia) 10/3/2025 2

3. Classification: Intravenous anesthetics: Are generally employed: To induce anesthesia ( act rapidly, with few seconds ), To provide supplemental anesthesia, or To permit anesthesia for short operative procedures Inhalational anesthetics: Used for longer-term maintenance of the anesthetic state 10/3/2025 3

4. Intravenous Anesthetic Agents: Their principal use is to induce anesthesia Ultra–short-acting barbiturates: E.g . Thiopental , methohexital Rapid entry into the CNS followed by relatively rapid redistribution, but Excellent hypnotic but Don't produce significant analgesia or muscle relaxation Thiopental is commonly used (Rapid and pleasant induction, low cost) Does not induce obstructive secretions in the airway, Produces little or no emesis, and Does not sensitize the myocardium to endogenous catecholamines 10/3/2025 4

5. Benzodiazepines: E.g. Midazolam , diazepam , and lorazepam The popularity of the benzodiazepines is related to their amnesic potential Midazolam is the most popular (Water soluble, short acting) Has a shorter half-life (t1/2 1.3–2.2 hours) May cause respiratory depression, apnea, S keletal muscle relaxation is inadequate Must be coadministered with analgesic and neuromuscular blocking agents . 10/3/2025 5

6. Etomidate ; Similar pharmacological effect to those of the barbiturates Provide a greater margin of safety(limited effects on the CV and respiratory systems) Short elimination half-life (t1/2 2.9 hours) Preserve cardiovascular and respiratory stability; (advantage to the patient with compromised myocardial oxygen or blood supply) ADRs: May cause pain on injection and May produce myoclonic muscle movements( 40%) 10/3/2025 6

7. Propofol : Is rapidly acting, Has a short recovery time, and Possesses antiemetic properties It is primarily a hypnotic drug, with Substantial cardio respiratory depressant actions Lacks analgesic properties Causes a significant reduction in blood pressure Should be used with utmost caution in patients with cardiac disease 10/3/2025 7

8. Ketamine: Pharmacologically quite different from other IV anesthetics Characterized as dissociative (i.e., the patient may appear awake and reactive but does not respond to sensory stimuli) Has profound analgesia, amnesia, and superficial level of sleep Interacts with the N-methyl-D-aspartate receptor It also stimulates the central sympathetic outflow (beneficial in patients with either hypovolemic or cardiogenic shock ) Employed mainly in children and young adults for short procedures It is lipophilic and enters the brain circulation very quickly 10/3/2025 8

9. Opioids : Frequently used together with anesthetics for their analgesic property The most frequently employed opioids are: Fentanyl , sufentanil or remifentanil They induce analgesia more rapidly than morphine does Administered either IV, epidurally , or intrathecally They can all cause hypotension, respiratory depression, and muscle rigidity Postanesthetic nausea and vomiting 10/3/2025 9

10. Inhalation Anesthetics: Are used primarily for maintenance of anesthesia The depth of anesthesia can be rapidly altered Reversible (rapidly eliminated from the body by exhalation) Common features: Nonflammable, non explosive Decrease cerebrovascular resistance , Their potency is defined quantitatively as the median alveolar concentration (MAC) Volatile liquids ( e.g. halothane, sevoflurane , enflurane , isoflurane , desflurane ) Gases at room temperature ( N2O and cyclopropane ) 10/3/2025 10

11. Halothane: Depresses respiratory function Potent anesthetic, but it is a relatively weak analgesic Co-administered with N2O, opioids , or local anesthetics Relaxes both skeletal and uterine muscle Suitable in children for inhalation induction (pleasant odor, not hepatotoxic in pediatric) 10/3/2025 11

12. Metabolized to tissue-toxic hydrocarbons ( trifluoroethanol ) and bromide ion) Responsible for the toxic reactions(fever, followed by anorexia, nausea, and vomiting), Patients may exhibit signs of hepatitis Adverse effects: Cardiac effects- Vagomimetic ( bradycardia ) Produces concentration-dependent hypotension Malignant hyperthermia- Treated with dantrolene 10/3/2025 12

13. Methoxyflurane : Is the most potent inhalational agent available High solubility in tissues (limits its use) Similar pharmacological properties with halothane Does not depress cardiovascular reflexes 10/3/2025 13

14. Enflurane: Less potent than halothane, Produces rapid induction and recovery Contraindicated in patients with kidney failure( fluoride ion production) Fewer arrhythmias, Less sensitization of the heart to catecholamines , Greater potentiation of muscle relaxants ( more potent curare-like effect) Causes CNS excitation 10/3/2025 14

15. Poorly metabolized in the liver, thus Less toxic than halothane It causes seizure during induction and following recovery from anesthesia Isoflurane : Is a structural isomer of enflurane Produces similar pharmacological properties Has analgesia, Some neuromuscular blockade, and Depressed respiration 10/3/2025 15

16. Nitrous oxide: Oderless and colourless gas It is rapid in action and also an effective analgesic agent Its potency is low, hence must be combined with other agents It is a relatively free of serious unwanted effects Ether: Has analgesic and muscle relaxant properties It is highly explosive, causes respiratory tract irritant 10/3/2025 16

17. II. Local Anesthetics: Are agents that reversibly block impulse conduction along nerve axons and other excitable membranes This action stabilizes and reduces excitability of cell membranes Involve loss of sensation and motor activity in localized areas of the body They can provide highly effective analgesia in well-defined regions of the body 10/3/2025 17

18. Properties of Local anesthetics Important properties of the ideal local anesthetic include: Low systemic toxicity at an effective concentration It should be effective both when injected into tissue and when applied topically to mucous membranes Onset of action should be quick, Duration of action should be sufficient Should be soluble in water and stable in solution Its effects should be completely reversible Note: No single compound available possessing all these properties 10/3/2025 18

19. Chemistry: 10/3/2025 19 Fig. 1 Model structure of local anesthetics showing aromatic portion, intermediate chain, and amine portion

20. Are weak bases and clinically available as salts to increase solubility and stability In the body they exist either as the uncharged base or as a cation The cationic form is the most active form at the receptor site Classification The ester agents- E.g. Cocaine, procaine, amethocaine and chloroprocaine , The amides- E.g. Lignocaine, prilocaine , mepivacaine and bupivacaine Have longer duration of action 10/3/2025 20

21. Mechanism of Action: Block the initiation and propagation of action potentials by preventing the voltage-dependent increase in Na + conductance Inhibit the inward migration of Na + Elevates the threshold for electrical excitation, Reduces the rate of rise of the action potential, Slows the propagation of the impulse, Completely blocks conduction(at high coc .) 10/3/2025 21

22. Prolongation of Action by Vasoconstrictors: Epinephrine, is often added to local anesthetics Performs a dual service: 1. Decreasing the rate of absorption, Localizes the anesthetic at the desired site, Prolong anesthetic effects, control bleeding The rate at which it is destroyed in the body 2. Reduces its systemic toxicity 10/3/2025 22

23. Adverse Effects Initially high doses produce CNS stimulation characterized by: Restlessness, disorientation, tremors, Continued exposure results in: General CNS depression; Death occurs from respiratory failure Drug induced depression of cardiac conduction Such as AV and intra ventricular Severe hypotension and cardiac arrest Allergic reactions, such as red and itchy dermatitis or vesiculation 10/3/2025 23

24. Use and techniques….. … 10/3/2025 24

25. Characteristics of specific Las: ESTERS Cocaine Primarily useful because of the vasoconstrictions Has high potential for abuse, because of euphoria and CNS stimulatory effects; Too toxic for systemic use Effects occur in 1–5 min and last 30–60 min Lower concentrations are used for the eye, while The higher ones are used on the nasal and pharyngeal 25

26. Clinical Uses: Topical anesthesia of ear, nose, and throat Benzocaine Poorly water soluble Minimal systemic absorption Available in numerous preparations, including aerosol sprays, throat lozenges, rectal suppositories, lotions, and ointments Clinical Uses: Topical anesthesia of skin and mucous membrane to relieve pain and itching of sunburn, wounds, skin , earache,& hemorrhoids, 10/3/2025 26

27. Effects occur in 5 min or less and last 15–45 min May cause allergic reactions Procaine: It is not effective topically but Employed for infiltration, nerve block, and spinal anesthesia Rapidly metabolized With injection, effects occur in 2–5 min and last 15–60 min 10/3/2025 27

28. Tetracaine : Tetracaine is an ester of PABA Is an effective topical local anesthetic agent Commonly used for spinal (subarachnoid) anesthesia Epinephrine is frequently added to prolong the anesthesia More potent and more toxic than procaine and cocaine Has approximately a 5-minute onset and 2 to 3 hours of action Now rarely injected because of possible allergic reactions 10/3/2025 28

29. AMIDES Lidocaine hydrochloride Is the most commonly used local anesthetic Given topically and by injection IV to prevent or treat cardiac dysrhythmias Used in infiltration and regional nerve blocks, and for spinal and topical anesthesia Anesthetic action occurs more rapidly, and more intense, Duration of action is longer thanthat of proc aine Lidocaine 2.5% and prilocaine 2.5% -f ormulated to be absorbed through intact skin; Warning : Do not use preparations containing epinephrine for dysrhythmias 10/3/2025 29

30. Bupivacaine: Given by injection May cause systemic toxicity Effects occur in 5 min and last 2–4 hours with injection, 10–20 min and 3–5 hours with epidural administration Has particularly long action, and some nerve blocks last more than 24 hours; This is often an advantage for postoperative analgesia. 10/3/2025 30

31. Difference between General & Local anesthetics GA LA Site of action : CNS Peripheral nerves Consciousness: Lost Unaltered Area of body involved: Whole body Restricted area Preferential use: Major surgery Minor surgery 10/3/2025 31

32. Pharmacology of Pain Medication (NSAIDs and Opioid Analgesics) The analgesic–antipyretic–anti-inflammatory drug group includes chemically and pharmacologically diverse drugs that Share the ability to relieve pain, fever, and/or inflammation. Some times called the Aspirin, NSAIDs, and Acetaminophen Are among the most widely used of all drugs Now more than 50 different NSAIDs on the global market 10/3/2025 32

33. I. NSAIDs Chemical groups and Examples: 1 . Salicylates: Aspirin, Sodium salicylate , Magnesiumsalicylate , Methylsalicylate 2. Propionic acid derivatives : Ibuprofen,Fenoprofen , Flurbiprofen,Ketoprofen 3. Acetic acid derivatives: Indomethacin,Tolmetin , Sulindac 4. COX-2 inhibitors: Rofecoxib , Celecoxib , Valdecoxib 5. Phenylbutazone : Antipyrine , Phenylbutazone , Dipyrone 6 . Oxicams : Meloxicam , Piroxicam , 7.Paraminophenol (Acetaminophen [in USA]: Paracetamol 8. Phenylacetic acid derivative : Diclofenac 10/3/2025 33

34. MECHANISM OF ACTION Aspirin, NSAIDs, and acetaminophen inactivate cyclooxygenases ( COX1, COX2 & COX3) To relieve fever, the drugs act on the hypothalamus to decrease its response to pyrogens . Largely through inhibition of prostaglandin production in the hypothalamus. For inflammation, they prevent prostaglandins from increasing the pain and edema produced by other substances released. 10/3/2025 34

35. At higher concentrations, NSAIDs : Reduce Production of superoxide radicals, Induce apoptosis, Inhibit the expression of adhesion molecules, Decrease nitric oxide synthase , Decrease proinflammatory cytokines ( e.g., TNF-a, interleukin-1), 10/3/2025 35

36. Beneficial actions due to PG synthesis inhibition : Analgesia: prevention of pain nerve ending sensitization Antipyretic Anti-inflammatory Antithrombotic Closure of ductus arteriosus in newborn Shared toxicities due to PG synthesis inhibition Gastric mucosal damage Bleeding: inhibition of platelet function Limitation of renal blood flow : Na+ and water retention Delay/prolongation of labour Asthma and anaphylactoid reactions in susceptible individuals 10/3/2025 36

37. 10/3/2025 37 Table- Features of nonselective COX inhibitors and selective COX-2 inhibitors

38. Indications for Use: NSAIDs are widely used to prevent and treat: Mild to moderate pain and/or inflammation associated with musculoskeletal disorders E.g . osteoarthritis, rheumatoid arthritis, gout, Headache, dysmenorrhea, minor trauma E.g ., athletic injuries such as sprains, myalgia , muscle strain, tendinitis, and bursitis, Minor surgery E.g . , dental extraction, episiotomy Fever, 10/3/2025 38

39. Adverse Effects: Mechanism-based side effects. These include: Gastric irritation, which may range from simple discomfort to ulcer formation An effect on renal blood flow in the compromised kidney - cause fluid retention A tendency to prolong bleeding Provoke hypersensitivity reactions, including bronchospasm, aggravation of asthma, urticarial Delayed parturition, dystocia (Uterine) Premature closure of the fetal ducus arteriosus . 10/3/2025 39

40. ADRs that are not related to inhibition of PGs synthesis include : Hepatic effects -Hepatitis, hepatic necrosis, cholestatic jaundice, increased serum aminotransferases , Dermal effects - Photosensitivities , Stevens-Johnson syndrome, toxic epidermal onycholysis CNS effects -Headaches, dizziness, tinnitus, deafness, drowsiness, confusion, nervousness, Ocular effects - Toxic amblyopia , retinal disturbances , 10/3/2025 40

41. Comorbid conditions aggravated by NSAIDs Peptic ulcer Hypertension Congestive heart failure Renal insufficiency Hemostatic disorders 10/3/2025 41

42. Contraindications and Drug Interactions History of ulcer disease, advanced age, poor health status, Smoking, and heavy alcohol use Used with caution in patients with renal impairment, heart failure, hypertension, and edema Concomitant treatment with corticosteroids (long term), other NSAIDs Should be used during pregnancy only if the potential benefit justifies the risk to the fetus . 10/3/2025 42

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44. Can increase the nephrotoxicity of agents such as aminoglycosides , amphotericin B, cidofovir , cisplatin , cyclosporine . Decrease effects of ACE inhibitors, beta blockers, and diuretics. Increase effects of anticoagulants, phenytoin With Agents that cause thrombocytopenia (e.g., myelosuppressive antineoplastic drugs) With methotrexate , risks of toxicity (bone marrow suppression, nephrotoxicity )- decrease the clearance 10/3/2025 44

45. Specific Nonsteroidal Antiinflammatory Drugs: Salicylates Aspirin and sodium salicylate are the most commonly used Aspirin is effective in pain of low to moderate intensity Are useful in the treatment of minor musculoskeletal disorders such as bursitis, synovitis , tendinitis, myositis , and myalgia Can be used in the treatment of inflammatory disease, such as acute rheumatic fever, RA, OA 10/3/2025 45

46. Aspirin is available as capsules, tablets, enteric-coated tablets , timed-release tablets buffered tablets , and as rectal suppositories. Regular aspirin tablets are well absorbed after oral administration . Their action starts within 15 to 30 minutes, peaks in 1 to 2 hours, and lasts 4 to 6 hours. Absorption of enteric-coated aspirin and rectal suppositories is slower and less complete. 10/3/2025 46

47. Aspirin is distributed to all body tissues and fluids, Binds to albumin (75 to 90%) Aspirin has a short half-life of 15–20 minutes but, Salicylic acid has a half-life of 2 to 3 hours at lower dose. It undergoes oxidation and conjugation in the liver and its metabolites are excreted through the kidneys. 10/3/2025 47

48. Routes and Dosage Ranges Pain, fever : PO 325–650 mg q4h PRN; usual single dose,650 mg OA, RA : PO 2–6 g/d in divided doses Prophylaxis of MI, and stroke : PO 81–325 mg/d Acute rheumatic fever : PO 5–8 g/d, in divided doses Unwanted effects Shares many of the general unwanted effects of NSAIDs Salicylism - characterized by tinnitus, vertigo, decreased hearing, and sometimes also nausea and vomiting Reye's syndrome, a rare disorder of children 10/3/2025 48

49. Indomethacin: Used in the treatment of acute gouty arhritis , RA,OA ,and spondylitis It is not recommended for use as a simple analgesic or antipyretic It produces more CNS side effects (vertigo, confusion, and psychological disturbances) Hematopoietic side effects: E.g . Leucopenia, hemolytic anemia, aplastic anemia, purpura, thrombocytopenia, and agranulocytosis ) Dosage : PO, rectal suppository, 75 mg/d initially, increased by 25 mg/d at weekly intervals to a maximum of 150–200 mg/d, if necessary 10/3/2025 49

50. Diclofenac: Is chemically different from but pharmacologically similar to other NSAIDs Is approved for use in RA, OA, ankylosing spondylitis , dysmenorrhea, and Topically for the treatment of ocular inflammation and actinic keratosis Has a serum half life of about 2 hours and is excreted mainly in the urine Dosage: OA: PO 100–150 mg/d in divided doses or 100 mg once daily RA: PO 150–200 mg/d in two, three or four divided doses AS: PO 100–125 mg/d in four or five divided doses Pain, dysmenorrhea: ( diclofenac potassium only) PO 50 mg three times daily 10/3/2025 50

51. PARACETAMOL (Acetaminophen [in USA]) Paracetamol is one of the most commonly used non-narcotic analgesic-antipyretic agents Inhibit CNS prostaglandin synthesis by inhibiting COX3 It has only weak antiinflammatory activity Thus, it is not useful in the treatment of rheumatoid arthritis and other inflammatory conditions Has two major advantages over aspirin: Does not cause gastric irritation or Does not Increase the risk of bleeding It is the drug of choice for: Children with febrile illness Elderly adults with impaired renal function and Pregnant women 10/3/2025 51

52. The major drawback to acetaminophen use is potentially fatal liver damage with overdose Thus it is not the drug of choice for people with: Hepatitis or other liver disorders or Those who drink substantial amounts of alcoholic beverages Routes and Dosage Ranges: Adult :PO 1000 mg three or four times per day ; maximum 4 g/d Children: PO 10 mg/kg 10/3/2025 52

53. II. Opioid Analgesics and Antagonist Pain is unpleasant sensory and emotional experience associated with: Actual or potential tissue damage or Described in terms of such damage Analgesics [ pain killers] can be classified as: Narcotic (Opioid) analgesics: Produce narcosis ( unconsciousness or stupor) Used only to relieve severe pain since there is problem of dependence and tolerance with repeated use of the drugs. Non-narcotic (mild) analgesics Are used to relief mild pain such as headache and toothache. 10/3/2025 53

54. Opioid Analgesics Obtained from the poppy, Papaver somniferum (Opium) Act on classical opioid receptor types -mu, and kapa , The drugs include: Opium alkaloids-Morphine and codeine Semisynthetics - Heroin and apomorphine Synthetic drugs-Methadone, fentanyl, alfentanil , sufentanil , meperidine, pentazosine , 10/3/2025 54

55. Pharmacological Effects: 1. Central effects Analgesia ,Euphoria, Sedation Respiratory depression (by acting centrally in medulla oblongata). Antitussive effects Miosis, or the pinpoint pupillary response Nausea and vomiting (stimulate chemoreceptor zone or vomiting centre found in medulla oblongata). 10/3/2025 55

56. 2. Peripheral effects Bradycardia and hypotension, (at larger dose) In the GIT, they produce constipation May precipitate urinary retention and prolong labor Induce the release of histamine, (itching sensation and bronchiolar constriction) Immunosuppressive, effects on the T helper cells 10/3/2025 56

57. Morphine: It is a naturally occurring alkaloid It has poor absorption from the GIT due to significant first-pass metabolism. Therefore it is administered by IV, SC and IM. Has least lipid solubility, and thus penetrates BBB slowly Used during severe pain, which is due to trauma, cancer, infarction, postoperative pain, etc . Respiratory depression is its major adverse effect . 10/3/2025 57

58. Methadone: It has similar pharmacodynamics profile with morphine Has longer action Effective after oral administration Tolerance and dependence develop slowly and therefore used therapeutically for controlled withdrawal of addicts on heroin and morphine 10/3/2025 58

59. Meperidine : It is less potent than morphine Unlike other opioid analgesics, it does not cause pin-point pupil It has significant antimuscarinic effect and thus contraindicated in patients with tachycardia It is well absorbed from GIT but has shorter duration of action 10/3/2025 59

60. Fentanil, Sulfentanil, Alfentanil and Rimefentanil Fentanil is more potent than morphine and sulfentanil is more potent than fentanil Their main use is in anaesthesia , and they may be given intrathecally . They have rapid onset and short duration of action 10/3/2025 60

61. Codeine: It is a much less potent analgesic but has a higher oral efficacy It shows a good antitussive activity at dose that does not cause analgesia Codeine has lower abuse potential than morphine because it produces less euphoria Therapeutically, it is used as antitussive For its analgesic effect, it should be combined with mild analgesics such as Aspirin and Paracetamol. 10/3/2025 61

62. Opioid antagonists: Naloxone It is a short-acting used to reverse the coma and respiratory depression of opioid overdose Naltrexone Naltrexone is very similar to naloxone Much longer duration of action ( t1/2 about 10 hours) It may be of value in addicts who have been 'detoxified', since it nullifies the effect of a dose of opiate It is also used in chronic alcoholics because it relieves craving  10/3/2025 62