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

3. Benzodiazepines (BZ) • Midazolam, lorazepam, and diazepam. • Primary uses: sedation, amnesia, anxiolysis 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.

4. Pharmacodynamics • CNS • Amnestic, anticonvulsant, anxiolytic, 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

5. 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.

6. 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

7. 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.

8. 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).

9. 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. • Respiratory system • Dose-dependent decreases in (RR) and (TV).

10. 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, • Airway surgery when periods of apnoeic oxygenation are employed).

11. 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).

12. 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.

13. 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; • Respiratory system • Dose-dependent decreases in RR and TV.

14. 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

15. Ketamine A sedative-hypnotic agent with potent analgesic properties Primary uses: • Induction ofGA. • Sedation and analgesia . • Mechanism:NMDA receptor antagonist

16. 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.

17. Pharmacodynamics: • CNS • Amnesia and profound analgesia. • ↑(CBF), ↑ (CMR),and ↑(ICP) pressure. • Cardiovascular system • ↑HR, and BP. • Direct myocardial stimulation & a central sympathetic effect • Used in hemodynamically compromised patients. • Respiratory system • Minimal respiratory depression • Potent bronchodilator .

18. 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

19. 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.

20. 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). N.B Useful in elderly and shocked patients

21. Adverse effects • Myoclonus. • Excitatory phenomena (e.g. involuntary limb twitches); • PONV; • Venous irritation and superficial thrombophlebitis • 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.

22. 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

23. 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 .

24. 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.

25. 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

26. 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).

27. Dexmedetomidine • Highly selective α2-adrenergic receptor agonist. • A sedative agent with analgesic properties. • A sedated but arousable state similar to natural sleep. • Minimal respiratory depression, • Weak amnestic; • No anticonvulsant properties. • Airway reflexes remain intact. • Metabolized extensively in the liver.

29. 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.

30. Characteristics of the ideal inhaled anesthetic agent • Non-toxic. • Non-flammable. • Non-allergenic. • Not a malignant hyperthermia (MH) trigger. • Stable in storage • 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

31. 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 0.75%, Isoflurane1.15% , Sevoflurane1.85%, Desflurane 6.0% at one atmosphere

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

33. 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%.

34. 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

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

36. Isoflurane: Advantages: • It causes peripheral vasodilation • ↓ BP, ↓ (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).

37. Sevoflurane • 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. • ↓blood pressure and SVR

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

39. 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

40. Nitrous Oxide MAC is 104% at one atmosphere CNS Mechanism: antagonism of NMDA receptors in CNS.- Weak anesthetic, produce analgesia • Cardiovascular system- HR and BP are usually unchanged.- ↑pulmonary vascular resistance. • Nausea/vomiting; • Risk of bone marrow depression • Respiratory system.Little effect on respiration

41. Inhibits vitamin B-12 metabolism • 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.

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

43. Neuromuscular blockers

44. Depolarizing(Succinycholine) • Structurally similar to acetylcholine … activate the acetylcholine receptors (Ach) depolarization of postjunctional membrane. • Fastest onset (60 s) • Very short duration of action • A short time intubation (Rapid sequence induction) • Metabolized very quickly by plasma cholinesterase. • Characterized by • Transient muscle fasciculations followed by relaxation. • Acetylcholine esterase (AChE) inhibitors potentiate rather than reverse the block.

45. Side effects of Succinycholine: • Myalgia : abdomen, back, and neck • Cardiac dysrhythmias.sinus bradycardia, junctional rhythm, and even asystole after the first dose in children and following repeated dose within a short time interval in adults • Hyperkalemia -Major burns, renal failure -Massive tissue injuries, muscular dystrophies • Extensive denervation of skeletal muscle, • upper motor neuron diseases. • A transient increase in intraocular pressure

46. Increased intragastric pressure • Increase in intracranial pressure.  • Succinycholine apnea (Prolonged blockade): -Low levels of plasma cholinesterase as in -severe liver or kidney disease, • A drug-induced inhibition of its activity, • A genetically atypical enzyme. • Anaphylaxis. over 50% of anaphylactic reactions to NMBDs. • Malignant hyperthermia (MH).

47. Nondepolarizing blockers • They act by competitively blocking the binding of ACh to its receptors and inhibit muscular contraction. • It is characterized by : • Absence of fasciculations. • Reversal by AChE inhibitors. • Potentiation by other nondepolarizing NMBDs and volatile anesthetic agents. • a slower onset than suxamethonium • Highly ionized, poorly lipid soluble and protein bound at physiological pH

48. 2 types • Benzylisoquinoliniums, e.g.atracurium,cisatracurium,mivacurium • Aminosteroids, e.g.pancuronium,vecuronium,rocuronium

49. Mivacurium • Short-acting. • Rapidly hydrolyzed by plasma cholinesterase. • Histamine release causing a transient hypotension and tachycardia. • Used with caution in patients with known atypical plasma cholinesterase activity or using cholinesterase inhibitors.

50. Atracurium besylate (Tracrium) • Widely used and have an intermediate onset and duration of action . • Histamine release , • No direct cardiovascular effects. • Metabolismis spontaneouslyby Hofmann degradation and ester hydrolysis in the plasma, • Its duration of action is independent of renal and hepatic function. • A breakdown product of atracurium, (laudanosine) may accumulate and cause seizures