1. General Anesthesia Dr. Samar Hashem Office Hours: Tuesday 10:00 – 1:00

2. Definition: General anaesthetics are a group of drugs that produce loss of consciousness ; and, therefore, loss of all sensation. The absolute loss of sensation is termed as “anaesthesia” (derived from the Greek word meaning insensitivity or lack of feeling). General anaesthetics cause descending depression of the central nervous system ; starting with the cerebral cortex, the basal ganglia, the cerebellum and finally the spinal cord. These drugs are used in surgical operations to induce unconsciousness ; and thus abolish /stop the sensation of pain. I-General anesthesia I-General anesthetics-Pharm 803 2

3. Stages of General anesthesia: There are four stages of anesthesia : Analgesia (stage I)::  It lasts from onset of drowsiness to loss of eyelash reflex. Unconsciousness and loss of pain or analgesia is partial till the end of this stage. Excitement (stage II):  It is characterized by loss of consciousness, delirium & excitement, increase in involuntary activity, irregular breathing, hyper-secretion (therefore an anti-cholinergic is used). Induction agents are designed to move the patient quickly through this undesirable stage. Stage I and II together are referred to as induction. I-General anesthetics-Pharm 803 3

4. Stages of General anesthesia: Surgical anesthesia (stage III):  It is characterized by regular breathing, skeletal muscle relaxation, and diminished reflexes specially those of the spinal cord. This is the stage in which most of surgeries are performed. Medullary paralysis (stage IV):  This stage results from overdose toxicity that leads to depression of vital centers of medulla it may involve respiratory failure and collapse of the vital motor functions and therefore, lead to death.  Thus to achieve safe anesthesia: short stage 1, rapid stage 2 and NO stage 4 are required. I-General anesthetics-Pharm 803 4

5. Stages of anesthesia Amnesia sedation Hypnosis Coma Death Awake 5

6. General Anesthesia is subdivided into: 1-Inhalation anesthesia: a- Gaseous & b- Volatile (Halogenated, nonhalogenated hydrocarbons and ethers) 2- Intravenous anesthesia I-General anesthetics-Pharm 803 3- Combination anesthesia N.B.: General anesthesia is usually induced with intravenous anesthetics, and maintained with inhalation anesthetics. 6

7. A combination of inhalation, intravenous anesthetics and other adjuvant drugs is called “balanced anesthesia”. These are given before and after administration of a general anesthetic to achieve the goals of a “ balanced anesthesia”. This practice fulfills many of purposes such as: 1.Controlling pain is achieved by using strong narcotic analgesics such as morphine and fentanyl. The latter is used to induce unconsciousness thereby reducing the dose of the anesthetic used. 2.Reducing anxiety, benzodiazepines sedatives are used such as diazepam, lorazepam and midazolam. Adjuvant to General anesthesia or (Combined Anesthesia ) I-General anesthetics-Pharm 803 7

8. 8 3-Inhibiting respiratory secretion & salivation and to prevent hypotension, anti-cholinergics such as scopolamine and atropine are used. 4-Prevention of nausea and vomiting by using antiemetics such as promethazine and chlorpromazine. 5-Relaxing muscles for optimum surgical working by using skeletal muscle relaxants such as pancuronium.

9. Mechanism of action is largely unknown. The following are two of several theories postulated to explain their mechanism of action. 1-Meyer-Overton Theory: They assumed that solubilisation of lipophilic general anaesthetic in the lipid bilayer of the neuron causes its malfunction and anaesthetic effect when critical concentration of anaesthetic is reached. The first SAR studies conducted by Meyer and Overton in 1880s showed a distinct direct relationship between the anesthetic potency and solubility in olive oil (lipophilicity). The higher the lipophilicity, the faster the induction and recovery from anesthesia. Mechanism of Action of General Anesthetics I-General anesthetics-Pharm 803 9

10. Figure1 2-Interaction With ION Channels: They probably act either through: a)inhibition of NMDA and glutamate receptors controlled channels such as ketamine, halothane, isoflurane as shown in figure (1) or b)by activation of inhibitory GABA receptor controlled channels such as propofol, midazolam, thiopental as shown in figure (2). Mechanism of Action of General Anesthetics I-General anesthetics I-General anesthetics-Pharm 803 NMDA is N-Methyl-D-Aspartate while GABA is Gamma aminobutyric acid,ICF intracellular fluid, ECF extracellular fluid. 10

11. 1-blocking the NMDA and glutamate controlled channels. Glutamate or NMDA receptors in the CNS are activated by the excitatory amino acid neurotransmitter glutamate or NMDA. The activation of such receptors opens the channel allowing potassium ions to flow to the extra cellular fluid and sodium and calcium ions to flow into the nerve cell. The increased intracellular calcium ions concentration triggers a cascade that ends with the liberation of the neuronal messenger nitric oxide NO. Nitric oxide is an important mediator in consciousness. 11

12. 12 Ketamine produces anesthesia by blocking the NMDA controlled channels, located at the excitatory synapses on the pyramidal cells. Halothane specifically antagonizes the glutamate stimulated depolarization, while isoflurane decreases the glutamate release and enhances its removal from the synaptic cleft.

13. 2-Activation of the inhibitory GABA receptor controlled channel. Binding of GABA to their receptors located at the inhibitory synapses on the pyramidal cells, will open the chloride ion channel, leading to the influx of chloride ions and hyper polarization of the neuron. Benzodiazepines and barbiturates produce anesthesia, by allosterically enhancing of GABA opening of the chloride channel. Halothane and isoflurane inhibit the synaptic destruction of GABA, thereby increasing the GABA-ergic neurotransmission. 13

14. I-General anesthetics Ideal Inhalation anesthetic should be: Non inflammable, Potent, having wide margin of safety and low toxicity, Not affecting myocardial functions or respiration at anesthetic doses, with good muscle relaxation, With uncomplicated/pleasant induction and emergence, Inexpensive and easy to administer, Chemically & metabolically stable. So far, the ideal inhaled anesthetic has not been developed. I-General anesthetics-Pharm 803 14

15. I-General anesthetics 1-Inhalation Anesthetics (Pulmonary)  The volatile anesthetic is inhaled into the lungs, diffuses into the blood, and when equilibrium is reached, it diffuses into the tissues.  It was found that activity of the inhaled anesthetic depends on its lipophilicity (NOT chemical structure), so they are considered non-specific agents.  Recovering patient is achieved by stopping delivery of anesthetic.  Ether was the first used non-halogenated anesthetic but now it is obsolete as it is highly explosive, causing postoperative nausea and vomiting with slow onset and recovery. I-General anesthetics-Pharm 803 15

16. I-General anesthetics Several factors should be considered when choosing an anesthetic which include: 1-Potency and solubility in lipid: The most common way to measure the potency of inhaled anesthetic is by recording the Minimum Alveolar Concentration (MAC). It is reported as “the mean alveolar concentration at 1 atmosphere needed to abolish movement (to a painful stimuli) in 50% of subjects”. The higher the MAC value, the lower the potency. Most inhaled anesthetics have different solubilities in fat as predicted by their “oil: gas partition coefficient. More lipophilic anesthetics have higher potency. I-General anesthetics-Pharm 803 16

17. I-General anesthetics-Pharm 803 The lesser the MAC the greater the potency Halothane has a MAC of slightly less than 1 while Nitrous oxide has a MAC of around 105 Thus, halothane is much more potent. AnestheticMAC (%)Blood:GasOil:Gas Nitrous oxide 1040.461.1 Halothane0.752.4137 Enflurane1.681.898 Desflurane7.30.4218.7 Isoflurane1.151.4390.8 Sevoflurane2.10.6550 17

18. I-General anesthetics Several factors should be considered when choosing an anesthetic which include:  2-Solubility in blood:  The ideal general anesthetic should have low solubility in blood expressed as the “blood:gas partition coefficient”. It is defined as “the ratio of the concentration of the drug in the blood to the concentration of the drug in the gas phase i.e.,in the lungs.  For a drug to have a quick onset, the solubility in blood should be low thus saturation will occur quickly, and the drug can then move to the tissue compartment (blood acts as a reservoir that needs to be filled.) I-General anesthetics-Pharm 803 18

19. 19  3-Stability:  The early inhaled anesthetics such as ether suffered from stability problems, leading to explosions and operating room fires.  It was discovered that by halogenating the ether and the hydrocarbon anesthetics, the flammability and explosiveness were diminished.

20. I-General anesthetics 1-Inhalation Anesthetics Gaseous Anesthetics : Nitrous Oxide (N 2 O) It is called the “laughing gas”. It is of low activity required concentration is up to 80% (NOT used alone, used with halothane or isoflurane to decrease their doses to ½ or 2/3 of the dose), hence anesthesia could be accomplished with less adverse effects. I-General anesthetics-Pharm 803 20

21. I-General anesthetics Some physical & chemical properties of inhaled anesthetics (SAR): 1.Halogenations of HC & ethers increases anesthetic potency but it also increases risk of cardiac arrhythmias in the following order F<Cl<Br. 2.Ethers with an asymmetric halogenated carbon tend to be good anesthetic (eg. enflurane). 3.Halogenated methyl ethyl ethers (enflurane & isoflurane) are more stable, more potent & have better clinical profile than diethyl ethers I-General anesthetics-Pharm 803 21

22. 22 4-Flourination decreases flammability & boiling point and increases stability of adjacent halogenated carbons. 5-Presence of double bond tends to enhance chemical reactivity & toxicity. 6-Complete halogenations of alkane & ethers or full halogenations of end methyl groups decrease potency & enhance convulsant activity. These agents include halothane, enflurane, isoflurane, desflurane and methoxyflurane.

23. I-General anesthetics Volatile Halogenated Hydrocarbons Halothane (Fluothane) Chemical name: 2-Bromo-2-chloro-1,1,1-trifluro ethane Non-flammable volatile liquid. Packaged in amber bottles containing 0.01%thymol as stabilizer as it undergoes spontaneous oxidation to HCl+ HBr+ Br - + Cl - + COCl 2 (phosgene). High potency, volatility and chemical stability due to fluorine. With low blood/gas partition coefficient, therefore it produces rapid induction and rapid recovery. I-General anesthetics-Pharm 803 23

24. Metabolism of Halothane: Mostly eliminated intact but about 20% is metabolized as follows: CF 3 CHBrCl→ [CF 3 CBrClOH] →→→ CF 3 COCl +HBr Carbinol trifluro-acetylchloride →→→→ CF 3 COOH + HCl trifluroacetic acid Side effects: (narrow margin of safety) Falling of cardiac output, contractile force & blood pressure during its administration. Increased possibility of arrhythmias. It has a negative effect on liver function. On repeated use cause hepatotoxicity due to the metabolites produced (immunoreactive response is suggested). 24

25. I-General anesthetics 2- Halogenated Ethers These are poly-fluorinated ether anesthetics which have analgesic, muscle relaxant properties Desflurane and sevoflurane are largely replacing enflurane and isoflurane. I-General anesthetics-Pharm 803 25

26. EnfluraneIsofluraneDesflurane 2- Chloro-1,1,2- trifluoro-ethyl- difluromethyl ether 1-Chloro-2,2,2- trifluoroethyl difluoro methyl ether 1,2,2,2- Tetrafluroethyl- difluoro methyl ether Non-flammable liquid With a mild sweet odour Non flammable more pungent than Halothane. Non-flammable, liquid pungent odor 26

27. EnfluraneIsofluraneDesflurane Lower blood/gas P.C lead to (3/4 that of halothane): a)more rapid induction & recovery than halothane. It has low blood gas PC  rapid recovery from anesthesia Replacement of Cl in isoflurane with F,decrease blood/ gas P.C  twice rapid induction and recovery than isoflurane (for out- patient surgical procedures [1]or same day surgery) 27

28. EnfluraneIsofluraneDesflurane Rule: rate of metabolism is Br>Cl>F Being of low solubility; no more than 2-5% of an absorbed dose is metabolized to F - ions. F - ions and ‘”Difluromethoxy difluroacetic acid “metabolite causes renal toxicity -Only 0.2% is metabolized to F - ions & trifluoro acetic acid -It’s metabolized because it contains mainly F & Cl atoms C-F is a stable bond so only 0.02% of drug is metabolized to F - ions and TFA (trifluroacetic acid) thus the drug is not associated with hepato or neprotoxicty 28

29. EnfluraneIsofluraneDesflurane A) Decreased nephrotoxicity b)decreased arrhythmia Fewer cardiovascular effects than enflurane. It can be used safely without concern of arrythmia production. Neither kidney, nor liver damage has been reported. In high dose a)it causes convulsion (NOT used in patients with epileptic focus) b)it relaxes uterus so NOT used during labour 29

30. I-General anesthetics Metabolism of Enflurane: I-General anesthetics-Pharm 803 Difluro methoxy difluroacetic acid metabolite 30

31. I-General anesthetics Metabolism of isoflurane: I-General anesthetics-Pharm 803 31

32. I-General anesthetics 2-I.V. Anesthetics (Parapulomnary) Non-explosive solids  rapid loss of conscious but insufficient anesthesia [NOT used alone]. Oxygen administration is recommended  especially if Barbiturates or thiobarbiturates These include propofol, ketamine, thiopental, methohexital, and midazolam. I-General anesthetics-Pharm 803 32

33. 1-Propofol (Diprivan®)2-Ketamine (Ketalar®) 2,6- Di- isopropylphenol Dissociative or cataleptic Dissociative or cataleptic analgesia analgesia  Activates inhibitory GABA in CNS (allosteric binding to GABA receptors)  Rapid onset, hypnosis within1 min  Short acting (5 min)  Maintenance with volatile anesthetics  More effective than thiopental  Blocks NMDA controlled channels  Very potent, moderately rapid acting, short duration (10-25 min) Poorly H 2 O soluble: formulated in 1-2% emulsion in soybean oil or glycerol (to decrease venous irritation) Injected I.V. or taken I.M. 33

34. 1-Propofol (Diprivan®)2-Ketamine (Ketalar®)  Uses :  Used in outpatient surgical procedure[2] & patients suffering from respiratory depression  Useful antiemetic Uses: Can be used as a sole agent in minor surgical procedure that does NOT require muscle relaxation, or it is used to induce anesthesia which is maintained by inhalation anesthesia Drawbacks: transient hypotension (Caution in old patients) -Patients older than16 years  (27%) post operative adverse psychological experiences (i.e., producing wild dreams and hallucination during emergence may last for 24 hr (So, ONLY for children & infants) -Termination of action is due to redistribution from brain to other tissues. Metabolism: Glucuronide and sulfate conjugates in liver. Metabolism: 1-Major demethylated metabolite “Norketamine: “active”, long duration. 2-Also by hydroxylation followed by glucuronide conjugation. 34

35. I-General anesthetics Synthesis of Propofol : I-General anesthetics-Pharm 803 Metabolism of Propofol: 35

36. I-General anesthetics Ultra-short acting barbiturates Rapid action  used to initiate anesthesia [maintenance with volatile anesthetics], not used for maintenance of anesthesia due to the fear of respiratory depression. Long side chain at C 5   lipid solubility   penetration through BBB. I-General anesthetics-Pharm 803 36

37. I-General anesthetics-Pharm 803 3-Thiopental4-Methohexital It’s Sodium-5-ethyl-5-(1-methylbutyl)-2- thiobarbiturate. It’s Sodium-1-methyl-5-allyl-5-(1-methyl-2- pentynyl) barbiturate -increased lipophilicity due to Sulfur and the long side chain. -N-methylated  So, more concn. of lipid soluble non ionized form at physiological pH -higher lipid solubility due to the long side chain. It crosses BBB extremely rapidly and produces unconsciousness in 20-30 seconds then it undergoes partitioning from brain to body fat. Rapidly penetrate CNS after I.V admin, redistribute rapidly and undergo rapid metabolic inactivation 37

38. 3-Thiopental4-Methohexital Metabolism: oxidative desulfuration into “pentobarbital” (sedative hypnotic NOT anesthetic) Metabolism: 1)N-dealkylation N-dealkyalted metabolite is active and 3 times more potent 2)Hydroxylation at CH 2 α to triple bond (ω, ω-1) (Site of metab.) 38

39. I-General anesthetics Benzodiazepines I-General anesthetics-Pharm 803 5- Midazolam maleate  used for induction of anesthesia & pre-operative sedation  Mechanism : allosteric enhancing of GABA opening of Cl ¯ channels  Short duration ( due to metabolic hydroxylation then conjugation)  Maleate salt: to enhance solubility  N.B BDZ alone cannot produce surgical anesthesia, only used for induction. 39

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