Pharmacology of general anesthetics

1. بسم الله الرحمن الرحيم Pharmacology of general anesthetics Dr. Ashraf Arafat, MD Assistant Professor Department of Anesthesia, King Saud University

2. General anesthesiaLoss of consciousnessAmnesiaAnalgesiaMuscle relaxation

4. Benzodiazepines (BZ) • Midazolam, lorazepam, and diazepam. • Primary uses: sedation, amnesia, anxiolysis for premedication or as adjuncts to general anesthesia. • Mechanism.Enhance inhibitory neurotransmission by increasing the affinity of GABAA receptors for GABA. • Pharmacokinetics • Effects are terminated by redistribution. • All are metabolized in the liver. • Diazepam clearance is reduced in the elderly.

5. Pharmacodynamics • CNS • Amnestic, anticonvulsant, anxiolytic, muscle-relaxant, and sedative-hypnotic (dose-dependent manner). • No analgesia. • Cardiovascular system • Mild systemic vasodilation and ↓ in cardiac output. HR is usually unchanged. • Respiratory system • Mild dose-dependent ↓in RR and TV. • Respiratory depression may be more if administered with an opioid

6. Adverse effects • Pregnancy and labor • Risk of cleft lip and palate in the first trimester. • CNS depression in the neonate. • Superficial thrombophlebitis and injection painby diazepam and lorazepam.

7. Flumazenil  • A competitive antagonist at the benzodiazepine binding site of GABAA receptors in the CNS. • Reversal of sedative effects occurs within 2 minutes; peak effects at 10 minutes. • Half-life is shorter than the benzodiazepine

8. Barbiturates • Such as thiopental and methohexital(highly alkaline). • Mechanism. • Facilitate inhibitory neurotransmission by enhancing GABAA receptor function. • Primary Use: Induction of anesthesia Advantages: • Rapid onset (30 - 45 sec) • Short duration (5 – 8 min) initial dose; redistributed from brain to muscle; Pharmacokinetics Hepatic metabolism & elimination.

9. Pharmacodynamics • CNS • Dose-dependent CNS depression . • ↓ in (CMRO2)cause ↓ in ICP and (CBF). • Potent anticonvulsant properties • Cardiovascular system • Depress myocardial contractility, leading to dose-dependent ↓ in BP and cardiac output, • Baroreceptor reflexes remain largely intact;

10. Respiratory system • Dose-dependent decreases in RR and TV. • Apnea may result for 30 to 90 seconds after an induction dose. • Laryngeal reflexes are suppressed to a lesser degree compared with propofol; ….. high incidence of cough and laryngospasm.

11. Adverse effects • Allergy. • Absolutely contraindicated in Porphyria • Venous irritation and tissue damage • Thiopental can cause severe pain and tissue necrosis if injected extravascularly or intra-arterially. If intra-arterial administration occurs, heparin, vasodilators, and regional sympathetic blockade may be helpful in treatment. • Myoclonus and hiccups . • Less suitable for day case surgery OR maintenance of anaesthesia • Multiple doses or prolonged infusions may produce prolonged sedation or unconsciousness

12. Ketamine A sedative-hypnotic agent with potent analgesic properties • ‘Dissociative anaesthesia’ with loss of consciousness and profound analgesia . Primary uses: • Induction ofGA. • Sedation and analgesia . • Mechanism:NMDA receptor antagonist

13. Pharmacokinetics • Unconsciousness in 30 to 60 s after an IV. • Terminated by redistribution in 15 to 20 minutes. • Metabolized rapidly in the liver ; • Elimination half-life is 2 to 3 hours. • Repeated bolus doses or prolonged infusions result in accumulation.

14. Pharmacodynamics: • CNS • Produces a “dissociative” state accompanied by amnesia and profound analgesia. • ↑(CBF), ↑ (CMR),and ↑(ICP) pressure. • Cardiovascular system • ↑HR, and BP whilst COP is maintained. • Direct myocardial stimulation & a central sympathetic effect • Used in hemodynamically compromised patients. • Respiratory system • Minimal respiratory depression • Potent bronchodilator . • laryngeal/pharyngeal reflexes are preserved

15. Adverse effects • Oral secretions (increased salivation)  . • Emotional disturbance.agitation & hallucinations • ↑ Muscle tone:  increased uterine tone • ↑ ICP : contraindicated in patients with head trauma or intracranial hypertension. • Ocular effects. mydriasis, nystagmus, diplopia, and ↑ intraocular pressure. • PONV

16. Propofol (Diprivan) 1%(10 mg/mL)isotonic oil-in-water emulsion, which contains egg lecithin, glycerol, and soybean oil. Highly lipid soluble Primary uses: • A sedative/hypnotic (ICU) • Induction or maintenance of anesthesia Mechanism: Facilitates inhibitory neurotransmission by enhancing the function (GABAA) receptors in CNS . Pharmacokinetics: Hepatic and extrahepatic metabolism to inactive metabolites which are renally excreted.

17. Pharmacodynamics: • CNS • Induction : rapid onset of unconsciousness (30 to 45 seconds), followed by a rapid termination of effect by redistribution • Emergence is rapid (short distribution half-life (1–2 min). • Weak analgesic effects . • ↓(CBF) ↓ (ICP),↓(CMRO2).and ↓(CPP) due to markedly ↓ (MAP).

18. Anticonvulsant . • Less (PONV) occurs. • Cardiovascular system • Direct myocardial depression with ↓ SVR • Dose-dependent ↓ in preload, afterload, and contractility lead to ↓ in (BP) and COP. • Hypotensionmay be marked in hypovolemic, elderly, or hemodynamically compromised patients. • Heart rate (HR) is minimally affected, and baroreceptor reflex is blunted.

19. Respiratory system • Dose-dependent decreases in (RR) and (TV). • ↓Ventilatory responses to hypoxia and hypercarbia. • Apnoea is common. • Laryngeal and pharyngeal muscle relaxation

20. Advantages • Safe in porphyria; • Antiemetic properties • Use in day case surgery . • Total intravenous anaesthesia (TIVA) • Situations where volatile anaesthetics cannot be used (e.g. • Malignant hyperthermia (MH) patients, • Transfer of sedated patients, • Airway surgery when periods of apnoeic oxygenation are employed).

21. Adverse effects • Venous irritation. • Bacterial growth • Lipid disorders.used cautiously in disorders of lipid metabolism (e.g., hyperlipidemia and pancreatitis). • Myoclonus and hiccups Propofol infusion syndrome : a rare fatal disorder that occurs in critically ill patients (usually children) subjected to prolonged, high-dose propofol infusions. (Rhabdomyolysis, metabolic acidosis, cardiac failure, and renal failure).

22. Etomidate Primary use: Induction in patients w/ cardiovascular problems Mechanism: Facilitates inhibitory neurotransmission by enhancing GABAA receptor function. • Pharmacokinetics • Effects of a single bolus dose are terminated by redistribution. • Very high clearance in the liver and by circulating esterases to inactive metabolites.

23. Pharmacodynamics • CNS • No analgesic properties. • ↓(CBF), cerebral metabolic rate, (CMR), and (ICP), . • Cardiovascular system • Minimal changes in HR, BP, and COP. • Respiratory system • Dose-dependent ↓ in ( RR) & (TV). • Transient apnea may occur. N.B Useful in elderly and shocked patients

24. Adverse effects • Myoclonus. • Excitatory phenomena (e.g. involuntary limb twitches); • PONV; • Venous irritation and superficial thrombophlebitis may be caused by the propylene glycol vehicle. Minimized by administration into a free-flowing IV carrier infusion. • Adrenal suppression: Inhibits 11β-hydroxylase; - A single induction dose suppresses adrenal steroid synthesis for up to 24 hours. • Repeated doses or infusions is associated with increased mortality in ICU patients.

25. Opioids • Opioids produce moderate sedation and profound analgesia. • They exert their effects by binding with opioid receptors in CNS ( 3 major opioid receptors μ (mu), κ (kappa), and δ (delta). • Meperidine, Morphine, Alfentanil, Fentanyl, Sufentanil, Remifentanil Advantages: Minimal cardiac effects No myocardial depression

26. Fentanyl • A potent synthetic opioid agonist with between 100 times the analgesic potency of morphine. • Used in • Induction • Maintenance of GA • Supplement regional and spinal anesthesia. • Ability to maintain cardiac stability. Sufentanil citrate (Sufenta) • 10 times as potent as fentanyl •  Rapid elimination , • Relatively more rapid recovery as compared with fentanyl.

27. Alfentanil • Shorter duration of action compared to fentanyl and sufentanil, Remifentanil (Ultiva) • Ultra short acting and rapidly cleared • widespread extrahepatic metabolism by blood and tissue nonspecific esterases, Morphine • May produce hypotension and bronchoconstriction as a consequence of its histamine-releasing action. • Morphine may be a poor choice for a patient with renal failure.

28. Side effects • Nausea & vomiting • Drowsiness or sedation, • Respiratory depression, • Miosis, • Chest wall rigidity, • Bradycardia in large doses • Some peripheral vasodilation and histamine release -- hypotension • Constipation, • Urinary retention & biliary colic, • Slow gastric emptying • Tolerance & Dependence

29. Naloxone • A specific opiate receptor antagonist, binding the receptor • The effective dose is 1 to 4 μg/kg IV, and the duration of action is 30 to 45 minutes. • Dose may need to be repeated or an infusion Side effects - Reversal of analgesia,  nausea, vomiting, - Increased sympathetic nervous system activity, ( tachycardia, hypertension, pulmonary edema, and cardiac dysrhythmias).

30. Dexmedetomidine • Highly selective α2-adrenergic receptor agonist. • A sedative agent with analgesic properties. • A sedated but arousable state similar to natural sleep. • Weak amnestic; no anticonvulsant properties. • Airway reflexes remain intact. • Minimal respiratory depression, • Metabolized extensively in the liver. • Decreases HR and BP, although transient hypertension may occur after an IV bolus. • Side effects : Antimuscarinic effects (e.g., dry mouth and blurred vision)

32. History of Anesthesia • Joseph Priestly – discovers N2O in 1773 • William Morton, dentist – first demonstration of successful surgical anesthesia with ether1846 • Dr. John Snow administers chloroform to Queen Victoria (1853)– popularizes anesthesia for childbirth in UK He becomes the first anesthesia specialist.

33. Characteristics of the ideal inhaled anesthetic agent • Non-toxic. • Non-allergenic. • Not a malignant hyperthermia (MH) trigger. • Stable in storage, non-flammable. • No extra specialist equipment needed. • Low solubility in blood and tissues, • Analgesic • Lack of injury to vital tissues. • The lack of seizures, respiratory irritation, and circulatory stimulation; • Resistance to physical and metabolic degradation • No reaction with soda lime/breathing circuit

34. Factors affecting minimum alveolar concentration (MAC)

35. The minimum alveolar concentration (MAC) : the amount of vapour (%) needed to render 50% of spontaneously breathing patients unresponsive to a standard painful surgical stimulus. • MACis inversely proportional to potency. Halothane, isoflurane, sevoflurane, and desfluraneare 0.75%, 1.15%, 1.85%, and 6.0%at one atmosphere

36. Volatile anesthetics • Present as liquids at room temperature and pressure • Vaporized into gases for administration

37. General pharmacokinetics • The higher the vapor pressure, the more volatile the anesthetic. • Blood solubility determines the speed of build-up / elimination from blood / brain • Lower blood solubility means (faster induction/recovery) Inspired air → Alveolar air → Blood → Brain

38. Volatile anesthetics • Mechanism:Various ion channels in the CNS involved in synaptic transmission (including GABAA, glycine, and glutamate receptors) may play a role. • Metabolism:hepatic . • Exhalation:This is the predominant route of elimination: • CNS • Unconsciousness and amnesia . • ↑ cerebral blood flow (CBF). • ↑ intracranial pressure • BMR: reduced; a MAC of 2 reduces oxygen consumption by 30%.

39. Cardiovascular system • Myocardial depression and systemic vasodilation, reduce SVR . • Hypotensive effect, • Change in HR, (desflurane) • Sensitize the myocardium to the arrhythmogenic effects of catecholamines. • Neuromuscular system • Dose-dependent ↓ in skeletal muscle tone. -Potentiation of muscle relaxants. • All volatile anaesthetics may precipitate malignant hyperthermia (MH). A dramatic increase in body temperature, acidosis, electrolyte imbalance and shock

40. Hepatic system: ↓ hepatic perfusion. Rarely,(“halothane hepatitis”). • Renal system.↓renal blood flow . • Respiratory system • Dose-dependent respiratory depression • ↓TV↑RR • Airway irritation and, during light levels of anesthesia, may precipitate coughing, laryngospasm, or bronchospasm (sevoflurane makes it more suitable ) • Bronchodilator, (with the exception of desflurane). - Respiratory response to hypoxia and hypercarbia is reduced.

41. Isoflurane: Advantages: • It causes peripheral vasodilation • A drop in blood pressure, systemic vascular resistance (SVR) • Tachycardia (sympathetic stimulation) • Increased coronary blood flow . Disadvantages: • Moderate solubility, so recovery from anesthesia may be delayed • Isoflurane can make the heart “more sensitive” to circulating catecholamines (like epinephrine).

42. sevoflurane Advantages: • Low solubility in blood-- produces rapid induction and emergence • Non-irritant with Pleasant smelling (suitable for children) • Has good bronchodilating properties • Agent of choice in asthma, bronchitis, and COPD. • It causes bradycardia, blood pressure and SVR • Mild respiratory and cardiac suppression (cardiac output is maintained) Disadvantages: Carbon dioxide absorbents in anesthesia machines degrade sevoflurane to Compound A

43. Desflurane Advantages: • Rapid onset and recovery of anesthesia due to a low blood/gas solubility coefficient (0.42). • (outpatient procedures) • One of least metabolized to toxic byproducts Disadvantages: • Requires a special vaporizer • Pungent and irritating to the airway (leading to more coughing, laryngospasm) cannot be used for induction • It increases salivary and respiratory secretions • High inspired gas concentrations lead to a significant ↑in the patient’s BP & HR.

44. Halothane • Used for induction in children (sweet pleasant odor); Side effects: • Sensitizethe myocardium to the arrhythmogenic effects of catecholamines, • Myocardial depression, • “Halothane hepatitis” (rare) related to repeated exposure, • Blood pressure usually falls, . • Very soluble in blood and adipose • Prolonged emergence

45. Nitrous Oxide MAC is 104% at one atmosphere CNS Mechanism: antagonism of NMDA receptors in CNS.- Weak anesthetic, produce analgesia - Usually combined with other anesthetics. - Used alone e.g. dental procedures); • Cardiovascular system- Mild myocardial depressant & a mild sympathetic stimulant.- HR and BP are usually unchanged.- ↑pulmonary vascular resistance.Respiratory system.Little effect on respiration

46. Nausea/vomiting; • Risk of bone marrow depression • Inhibits vitamin B-12 metabolism • Second Gas Effect: Increased uptake of volatile agent when given together with N2O • Expansion of closed gas spaces.nitrous oxide is 35 times more soluble in blood than nitrogen, Contraindicated in (e.g. air embolus, pneumothorax, Middle Ear Surgery etc) Diffuse into the cuff of ETT. • Diffusion hypoxia.After discontinuation, its rapid elimination from the blood into the lung may lead to a low partial pressure of oxygen in the alveoli.

47. Xenon A gas and exhibits many properties of an ideal anaesthetic agent : • Colourless, • Odourless, • Non-flammable, • Stable in storage, • Low oil/gas and blood/gas coefficients, • Cardiovascularly stable, • Excreted unmetabolized, • Non-toxic, • MH safe Disadvantage : very expensive .

49. D. Neuromuscular blocking drugs Used to • Perform tracheal intubation, • Facilitate ventilation, • Provide optimal surgical operating conditions.

50. Neuromuscular blockers