GENERAL ANESTHETICS pharmacology.pptxxxx

about general anesthetic medicens

1. GENERAL ANESTHETICS

2. CONTENTS INTRODUCTION STAGES OF ANESTHESIA SITES AND MECHANISM OF ACTION INDUCTION AND RECOVERY SECOND GAS EFFECT PHARMACOLOGIC EFFECTS OF GENERAL ANESTHETICS GENERAL ANESTHETIC AGENTS

3. Anesthesia Anesthesia is a reversible condition induced by anesthetic drugs that is characterized by reduction or complete loss of response to pain or other sensation such as consciousness and muscle movements . Opioids, alcohol, cannabis → asphyxia and concussion → Inhalational agents (N 2 O) → Intravenous agents (thiopentone) → fluorinated hydrocarbons (halothane).

4. Stages of General anesthesia Stage of Analgesia : Analgesia, HR & BP normal, patient is conscious. Excitement : Depression of inhibitory neurons in CNS → Excitement involuntary muscle movements, pupillary dilation, ↑HR, ↑BP and ↑respiration. Surgical anesthesia : Gradual loss of muscle tone and reflexes Patient fully unconscious and unresponsive to surgery Ideal stage for surgery Medullary paralysis : Respiratory and cardiac failure, Death

5. SITES OF ACTION OF GAs Action on Thalamus and Reticular Activating System → reversible loss of consciousness Action on Hippocampus , Amygdala and Prefrontal cortex → Amnesia Action on the spinal cord → Immobility and Analgesia

6. THEORIES OF GA MECHANISM Distortion of lipid nerve membrane structure → hampers the ionic flow through channels → ↓neuronal excitability → ↓rate of rise of AP. GABA-A receptor → ↑CL - ion conductance → facilitates GABAergic neurotransmission [hypnotic effect]. Glycine gated Cl ion channels --- ↓neurotransmission.

7. BALANCED ANESTHESIA Preanesthetic medication (atropine, BZD, opioid analgesics). An agent for Induction (thiopentone sodium). An agent for Maintenance (N 2 O, halothane). Skeletal muscle relaxants.

8. CLASSIFICATION OF GENERAL ANESTHETICS

9. GENERAL ANESTHETIC AGENTS Based on abilities to produce analgesia, immobility and unconsciousness

10. EFFECTS OF GENERAL ANESTHESIA CNS CVS RESPIRATORY KIDNEY ↓ Metabolic rate in the brain ↑ Cerebral blood flow → ↑ intracranial tension. All halogenated gases reduce BP (↓COP or ↓PVR) All agents increase the rate of respiration except NO Inhaled anesthetics --- GFR and urine flow Least with N 2 O, most with N2O+Halothane Halothane → bradycardia (vagal stimulation) Enflurane → ↑ HR NO, Halothane → depresses myocardium dose dependently Bronchodilation → status asthmaticus Desflurane is irritant to airways Enflurane may cause seizure activity Halothane → cardiac arrythmias

11. INHALATIONAL AGENTS Nitrous oxide, xenon and cyclopropane. Produce significant analgesia . Weak effects on consciousness and immobility. Typically used in maintenance phase of anesthesia. Effects mediated through NMDA receptors (regulate pain) and 2-pore domain K + ion channels ( ↑ efflux of K + --- ↓ excitability )

12. NMDA RECEPTOR TRANSMISSION

13. MAC(MINIMUM ALVEOLAR CONCENTRATION) VALUE 1 MAC value is the alveolar concentration of drug that causes immobility in 50% of the subjects exposed to a strong noxious stimulus. MAC value is an indicator of efficacy of volatile anesthetic agents. Higher the MAC value, lower is the efficacy of the agent. N 2 O=105 (not able to produce full surgical anesthesia).

14. Second gas effect During induction of GA, when a large volume of gas (e.g. nitrous oxide) is taken up from alveoli into pulmonary capillary blood, the concentration of gases remaining in the alveoli is increased. This results in effects known as the ‘concentration effect’ and the second gas effect This effect occurs when a soluble first gas such as nitrous oxide is delivered in high inspired concentrations. Nitrous oxide enters the alveoli far more rapidly than nitrogen leaves, causing dilution of the gaseous contents of the alveolus. This results in the dilution of oxygen within the alveoli of patients breathing air and may cause ‘ diffusion hypoxia ’.

15. INDUCTION AND RECOVERY Blood/gas partition co-efficient : Inversely proportional to induction and recovery . Oil/Gas partition co-efficient : Higher value indicates higher rate of recovery. Physiological factors : alveolar ventilation rate, cardiac output and solubility of gas in tissues.

16. Nitrous Oxide (N 2 O) Colorless, odorless inorganic gas Very potent analgesic, quick induction and recovery. As a single agent, used in dental extraction procedures. Carrier or adjuvant to other anesthetics. Interaction with Vitamin B12 --- bone marrow depression Non-toxic to liver, kidney and brain.

17. HALOGENATED VOLATILE ANESTHETICS Halothane, enflurane, Isoflurane, sevoflurane and desflurane. Potent producers of immobility . Effects are mediated through a different subunit of GABA-A receptor as well as the 2 pore domain K + ion channels (affects immobility). Inhibition of NMDA receptors is also involved. Neuronal Ach receptors, 5-HT type 3 receptors, ATP sensitive K + ion channels etc.

18. G. Anesthetic Blood/gas coefficient Oil/gas coefficient MAC value Muscle relaxation Analgesia Sensitization to myocardium Halothane 2.3 224 0.75 Negligible Poor ++ Enflurane 1.9 98 1.68 Moderate Poor + Isoflurane 1.4 99 1.2 Moderate Poor Mild Desflurane 0.42 19 6.0 Moderate Poor Negligible Sevoflurane 0.68 50 2.0 Moderate Poor Negligible Nitrous Oxide 0.47 1.4 105 Poor Very good Nil PROPERTIES OF HALOGENATED VOLATILE ANESTHETICS

19. TOXICITY OF INHALATIONAL AGENTS HEPATOTOXICITY NEPHROTOXICITY Least risk with enflurane and sevoflurane Sevoflurane + soda lime --- toxic metabolite --- renal damage MALIGNANT HYPERTHERMIA Genetic disorder involving a hypermetabolic state of skeletal muscles Hyperthermia, severe muscle rigidity, hypertension, tachycardia Treated by dantrolene

20. INTRAVENOUS AGENTS Thiopentone, propofol and ketamine. Potent producers of unconsciousness . Commonly used in the induction phase . To be supplemented with analgesics and muscle relaxants. Effects mediated by GABAergic (GABA-A) neurotransmission. CNS excitement is bypassed

21. THIOPENTONE SODIUM Ultra short acting, duration 5-10 minutes. Very quick induction and recovery. No CNS excitement. Produces hyperalgesia, to be used with an analgesic. No muscle relaxant effect, to be used with a muscle relaxant for endotracheal intubation.

22. Propofol Short acting, used for induction and maintenance. Rapid induction. 10 fold faster recovery than thiopentone. Highly protein bound and metabolism by conjugation in liver. Used for OPD anesthesia and suitable for basal anesthesia.

23. Ketamine NMDA receptor antagonist. Analgesic property, poor muscle relaxation Usually used i.v. Used in dissociative anesthesia. Potent bronchodilator. Dressing of traumatic wounds and severe burns In combination with diazepam in cardiac catheterization, OPD surgical procedures

24. BENZODIAZEPINES Midazolam, lorazepam Action can be readily terminated by the use of selective antagonist Most commonly used for preoperative medication, iv sedation and anti-seizure activity. Midazolam is effective for premedication, sedation during regional anesthesia. May be used in combination with propofol and other opioid analgesics. Remimazolam is a newer benzodiazepine used for sedation in minor surgeries, dental and other medical procedures.

25. DEXMEDATOMIDINE Produces sedation and anesthesia without the risk of respiratory depression. Alpha-2 sub type ‘a’ adrenergic receptors --- inhibits adrenergic transmission --- ↓ propagation of pain signals & induces light sedation. AEs: Bradycardia, hypotension, transient hypertension.

26. ADVERSE EFFECTS OF IV GAs Etomidate: adrenal suppression and transient skeletal muscle movements. Propofol: respiratory depression, hypotension, anaphylactoid reaction. Barbiturates: apnea, cough, bronchospasms and respiratory depression. Ketamine: Hypertension, Increases intracranial and intraocular tension, psychomimetic reactions (vivid dreams, illusions, euphoria).

27. PROPERTIES OF INTRAVENOUS ANESTHETICS Source: Katzung and Trevor’s Basic and Clinical Pharmacology 13 th edition

28. Preanesthetic medication Anti-cholinergic drugs (atropine, hyoscine, glycopyrrolate). Decrease salivary and bronchial secretions Prevent vasovagal attack (bradycardia, hypotension) Benzodiazepines (diazepam, midazolam) Anxiolytic activity, sedation and amnesia. Neuroleptics (chlorpromazine, trifluoperazine) Sedation, relieve anxiety, anti-emetic action. Opioid analgesics (morphine, pethidine) Used in cases of severe pain

29. References Textbook of Medical Pharmacology by S K Srivastava. Katzung and Trevor’s Basic and Clinical pharmacology 13 th edition.

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