General and Local Anesthetics PDF

Central Nervous system pharmacology for medical students General and Local Anesthetics 1 Abenezer Aklog (B.Pharm, MSc.) General and Local Anesthetics Abenezer Aklog  General Anesthetics 2  Agents that...

Central Nervous system pharmacology for medical students General and Local Anesthetics 1 Abenezer Aklog (B.Pharm, MSc.) General and Local Anesthetics Abenezer Aklog  General Anesthetics 2  Agents that depress the CNS to a sufficient degree to permit the performance of surgery and unpleasant procedures  Have low therapeutic indices and thus require great care in administration  Selection of specific drugs and routes of administration depends on  Pharmacokinetic properties and  Secondary effects of the various drugs  Modern practice of anesthesiology relies on the use of combinations of intravenous and inhaled drugs (balanced anesthesia techniques) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 3  General principles of surgical anesthesia  Administration of general anesthesia driven by three general objectives Minimizing the potentially deleterious direct and indirect effects Sustaining physiologic homeostasis during surgical procedures Involve major blood loss, tissue ischemia, reperfusion of ischemic tissue, fluid shifts, exposure to a cold environment, and impaired coagulation Improving postoperative outcomes By choosing techniques that block or treat components of the surgical stress response, which may lead to short- or long-term sequelae General and Local Anesthetics Abenezer Aklog  General Anesth cont... 4  Hemodynamic effects of general anesthesia  Most prominent physiological effect of anesthesia induction is a decrease in systemic arterial blood pressure  The causes include;  Direct vasodilation Myocardial depression A blunting of baroreceptor control A generalized decrease in central sympathetic tone  Agents vary in the magnitude of their specific hypotensive effects General and Local Anesthetics Abenezer Aklog  General Anesth cont... 5  Respiratory effects of general anesthesia  Nearly all general anesthetics reduce or eliminate both ventilatory drive and the reflexes that maintain airway patency  Ventilation generally must be assisted or controlled during surgery  Lower esophageal sphincter tone also is reduced, so both passive and active regurgitation may occur  Endotracheal intubation has reduced the number of aspiration deaths Muscle relaxation is valuable to facilitate intubation  Alternatives to an endotracheal tube include a face mask and a laryngeal mask General and Local Anesthetics Abenezer Aklog  General Anesth cont... 6  Hypothermia  Patients commonly develop hypothermia (body temperature < 36°C) during surgery  Reasons include Low ambient temperature, Exposed body cavities, Cold intravenous fluids, Altered thermoregulatory control, and Reduced metabolic rate and O2 consumption- heat generation decreases  Prevention of hypothermia is a major goal of anesthetic care General and Local Anesthetics Abenezer Aklog  General Anesth cont... 7  Nausea and Vomiting  Continue to be significant problems following general anesthesia  Due to the action of anesthetics on the chemoreceptor trigger zone and the brainstem vomiting center  Modulated by 5HT, histamine, ACh, DA, and NK1  The 5HT3 R antagonists (ondansetron, dolasetron, and palonosetron) are effective in suppressing nausea and vomiting  Common preventive strategies include  Anesthetic induction with propofol;  Combined use of droperidol, metoclopramide, and dexamethasone; and  Avoidance of nitrous oxide (N2O). General and Local Anesthetics Abenezer Aklog  General Anesth cont... 8  Other emergent and Postoperative phenomena  Hypertension and tachycardia are common during emergence from anesthesia  As the sympathetic nervous system regains its tone  Myocardial ischemia can appear or worsen during emergence in patients with coronary artery disease  Emergence excitement occurs in 5%–30% of patients  Chxed by Tachycardia, Restlessness, crying, moaning  Postanesthesia shivering occurs frequently because of core hypothermia  All of these emergence phenomena is greatly reduced with opioids and α2 adrenergic agonists General and Local Anesthetics Abenezer Aklog  General Anesth cont... 9 Ideal properties of general anesthesia (Anesthetic state)  Amnesia  Analgesia  Sufficient to abolish the reflex reactions to pain, such as muscular movement and cardiovascular stimulation  Rapid loss of consciousness  It eliminates awareness, memory of pain, anxiety, and stress throughout the surgical period  Relaxation of skeletal muscle  Facilitate endotracheal intubation, and reduce the dose of anesthetic required to produce immobility  Attenuation of autonomic responses to noxious stimulation General and Local Anesthetics Abenezer Aklog  General Anesth cont... 10 The potency of general anesthetic agents is measured by determining the concentration of general anesthetic that prevents movement in response to surgical stimulation For inhalational anesthetics, anesthetic potency is measured in MAC units  MAC is the Minimum Alveolar Conce that prevents movement in response to surgical stimulation in 50% of subjects The potency of intravenous agents is defined as the free plasma concentration (at equilibrium) that produces loss of response to surgical incision (or other end points) in 50% of subjects General and Local Anesthetics Abenezer Aklog  General Anesth cont... 11 Mechanisms of Anesthesia “Unitary theory” – anesthesia is produced by perturbation of the physical properties of cell membranes Based on correlation b/n potency of an anesthetic and its lipid solubility –lipophilic is more potent (Meyer-Overton rule) Drawback- neglect the protein targets (Receptors) Contemporary hypothesis suggest that Different anesthetic agents produce specific components of anesthesia by actions at different molecular targets General and Local Anesthetics Abenezer Aklog  General Anesth cont... 12 Molecular Mechanisms of Anesthesia  General Anesthetics are majorly divided in to two  Inhalational (Halogenated Hydrocarbons except N2O)  Intravenous Anesthetics (Propofol, Barbiturates, Ketamine, Etomidate..)  Principal molecular targets are Ligand gated Ion channel  Enhancing inhibitory neurotransmission (activate GABAA R & K+) Halogenated inhalational and many IV anesthetics (except ketamine)  Suppress excitatory neurotransmission (block NMDA R) Ketamine, N2O, Xenon, and cyclopropane General and Local Anesthetics Abenezer Aklog 13 Putative targets of anesthetic action. Anesthetic drugs may (A) enhance inhibitory synaptic activity or (B) diminish excitatory activity. ACh, acetylcholine; GABAA, γ-aminobutyric acid-A. General and Local Anesthetics Abenezer Aklog  General Anesth cont... 14 Anatomic Sites of Anesthetic Action  GA interrupt nervous system function at myriad levels,  Peripheral sensory neurons, the spinal cord, the brainstem, and the cerebral cortex  Most GA cause a global reduction in Cerebral Metabolic Rate and in Cerebral Blood Flow.  Consistent feature of GA is a suppression of metabolism in the thalamus  Major relay by which sensory input from the periphery ascends to cortex  Serve as a switch between the awake and anesthetized states General and Local Anesthetics Abenezer Aklog  General Anesth cont... 15 Stages and depth of anesthesia  General anesthesia has three stages: Induction, Maintenance, and Recovery  Induction –Is the time from administration of a potent anesthetic to development of effective anesthesia  IV agents like Propofol are employed to induce G anesthesia (30-40sec)  Maintenance –provides sustained anesthesia  Provided with volatile anesthetics (HHC)  Recovery –Is the time from discontinuation of anesthetic until consciousness is regained. General and Local Anesthetics Abenezer Aklog  General Anesth cont... 16 Depth of anesthesia- Historical for ether  Has four sequential stages characterized by increasing CNS depression as the anesthetic accumulates in the brain  Stage I- “Analgesia”  Stage II- “Excitement”  Stage III- “Surgical Anesthesia”  Stage IV- “Medullary Paralysis” General and Local Anesthetics Abenezer Aklog  General Anesth cont... 17 Inhalational anesthetics  Can be Volatile liquids or Gases  Volatile Liquids Low vapor pressures Higher boiling points  Gases (N2O, Xe) High vapor pressures Low boiling points  Used for maintenance of anesthesia General and Local Anesthetics Abenezer Aklog  General Anesth cont... 18 Inhalational anesthetics (IA)  PHARMACOKINETICS  Inhaled anesthetics, both volatile and gaseous, are taken up through gas exchange in the alveoli of the lung  Uptake into the blood and distribution and partitioning in the effect compartments determine the kinetics of IA  An ideal anesthetic should have a rapid onset (induction) and offset (recovery)  Achieved through rapid change in the anesthetic conce in the CNS  Several factors determine the change in the anesthetic conce in the CNS General and Local Anesthetics Abenezer Aklog  General Anesth cont... 19  Uptake and Distribution A. Factors Controlling Uptake 1. Inspired concentration and ventilation  The driving force for uptake of an IA into the body is the ratio between inspired and alveolar concentration  Two parameters determine alveolar anesthetic conce.  Inspired concentration/Partial pressure  Alveolar Ventilation  To accelerate induction, anesthesiologists increase the inspired anesthetic partial pressure  Fractional rise of anesthetic partial pressure is usually expressed as a ratio of alveolar concentration (FA) over inspired concentration (FI) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 20 A. Factors Controlling Uptake 1. Inspired concentration and ventilation  Alveolar ventilation also directly determines the rate of rise of FA/FI  Increases with increasing tidal volume and respiratory rate  Magnitude of this effect is much greater for inhaled anesthetics with high blood solubility  As increased ventilation supplies more anesthetic molecules to the alveolus, a more soluble anesthetic (blood:gas partition coefficient > 1)  Will traverse the alveolar capillary membrane more readily, preventing a rise in its alveolar partial pressure  Increasing the ventilation will replenish alveolar partial pressure General and Local Anesthetics Abenezer Aklog  Effect of ventilation on FA/FI 21 and induction of anesthesia. Increased ventilation (from 2L/min to 8 L/min ) accelerates the rate of rise toward equilibration of both halothane and nitrous oxide but results in a larger percentage increase for halothane in the first few minutes of induction General and Local Anesthetics Abenezer Aklog  General Anesth cont... 22 A. Factors Controlling Uptake 2. Solubility  An important factor influencing the transfer of an anesthetic from the lungs to the arterial blood  Blood:gas partition coefficient is a useful index of solubility  It defines the relative affinity of an anesthetic for the blood compared to the affinity for inspired gas  An anesthetic with low blood solubility  Achieves equilibrium (FA/FI~1) quickly and blood conce rises rapidly  Opposite is true for anesthetic with moderate to high blood solubility General and Local Anesthetics Abenezer Aklog  Uptake of inhalational 23 general anesthetics. The alveolar anesthetic concentration (FA) approaches the inspired anesthetic concentration (FI) fastest for the least-soluble anesthetics (Nitrous oxide and Desflurane) and slowest with the most soluble anesthetic, Halothane General and Local Anesthetics Abenezer Aklog 24 General and Local Anesthetics Abenezer Aklog  General Anesth cont... 25 A. Factors Controlling Uptake and Distribution 3. Cardiac output  Changes in the flow rate of blood through the lungs also affect the uptake of anesthetic gases  Effect of cardiac output should be considered in combination with the tissue distribution and uptake of anesthetic into other tissue compartments  An increase in pulmonary blood flow (ie, increased CO) will increase the uptake of anesthetic, thereby slowing the rate by which FA/FI rises  Decreasing the rate of induction of anesthesia General and Local Anesthetics Abenezer Aklog  General Anesth cont... 26 A. Factors Controlling Uptake and Distribution 4. Alveolar-venous partial pressure difference  Depends mainly on uptake of the anesthetic by the tissues  Blood:Tissue pat. Coeff., rate of blood flow to tissues, and Conce. gradient  The greater the difference, the more time it will take to achieve equilibrium with brain tissue  Highly perfused organs (eg, brain, heart, liver, kidneys, and splanchnic bed) exert the greatest influence on the arteriovenous anesthetic concentration gradient during induction of anesthesia  Higher solubility of the anesthetic in this organs, decreases venous conce. and thereby, increase the time required for alveolar equilibrium General and Local Anesthetics Abenezer Aklog  General Anesth cont... 27 A. Factors Controlling Uptake and Distribution 4. Alveolar-venous partial pressure difference  Although muscle and skin constitute 50% of the total body mass, anesthetics accumulate more slowly in these tissues than in highly perfused tissues (eg, brain)  Receive only one fifth of Distribution of anesthetic agent to different tissue based the resting CO on perfusion rate General and Local Anesthetics Abenezer Aklog  General Anesth cont... 28 B. Elimination  Recovery from inhalation anesthesia follows some of the same principles in reverse that are important during induction  Rate of elimination of the anesthetic from the brain determines the time to recovery from inhalational anesthetics  Factors determining recovery  Blood:gas partition coefficient- most important factor  Pulmonary blood flow and  Tissue solubility of the anesthetic  Duration of anesthetic administration General and Local Anesthetics Abenezer Aklog  General Anesth cont... 29 B. Elimination  Two features differentiate the recovery phase from the induction phase  Induction can be enhanced by increasing anesthetic conce. But not recovery  Anesthetic tension is zero in all tissues at induction but it varies in different tissues during recovery  As in induction, Ventilation also enhances recovery (emergence from anesthetic state)  The effect of metabolism for elimination is less for modern inhaled anesthetics  But Halothane is metabolized in the liver (may cause Hepatotoxicity) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 30  Specific inhalational Anesthetics  Halothane  It is a volatile liquid at room temperature (stored in a sealed container)  It is a light-sensitive and marketed in amber bottles with thymol preservative  Pharmacokinetics  Has relatively high blood:gas and high fat:blood partition coefficient  Induction therefore is relatively slow  The speed of recovery is lengthened as a function of duration of administration General and Local Anesthetics Abenezer Aklog  General Anesth cont... 31  Specific inhalational Anesthetics  Pharmacokinetics  Approx. 60-80% of halothane taken up by the body is eliminated unchanged by the lungs, the rest is biotransformed by hepatic CYPs  The major metabolite of halothane is trifluoroacetic acid, which is formed by removal of bromine and chlorine ions  Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, trifluroacetylate several protiens in the liver  Immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis General and Local Anesthetics Abenezer Aklog  General Anesth cont... 32  Specific inhalational Anesthetics  Clinical Use  Potent agent usually used for maintenance of anesthesia (weak analgesic)  Not pungent and is therefore well tolerated for inhalation induction of anesthesia  Extensively used in children because it is Well tolerated for inhalation induction and The serious side effects appear to be diminished in children  Potent bronchodilator and also relaxes both skeletal and uterine muscles General and Local Anesthetics Abenezer Aklog  General Anesth cont... 33  Specific inhalational Anesthetics  Side Effects o CVS  Dose-dependent reduction in arterial blood pressure  By Myocardial depression (Vagomimetic effect) that reduce CO o Respiratory Effects  Cause concentration-dependent inhibition of the ventilatory response to Hypercapnia and Hypoxia  Respiratory depressant effect overcome by mechanical ventilation General and Local Anesthetics Abenezer Aklog  General Anesth cont... 34  Specific inhalational Anesthetics  Side Effects o Nervous system  Dilates the cerebral vasculature, increasing cerebral blood flow  Increase intracranial (IC) pressure in pts with brain edema or IC HTN o Muscle  Potentiates the actions of non-depolarizing muscle relaxants (curariform drugs)  Increases both their duration of action and the magnitude of their effect General and Local Anesthetics Abenezer Aklog  General Anesth cont... 35  Specific inhalational Anesthetics  Side Effects o Muscle  May induce malignant hyperthermia (MH), fatal heritable genetic disorder  Caused by an increase in free cytosolic calcium concentration in skeletal muscle cells  MH is due to an excitation–contraction coupling defect  Chrxed by Muscle rigidity, hyperthermia, rapid onset of tachycardia and hypercapnia, hyperkalemia, and metabolic acidosis  Mgt –D/C the anesthetic and give Dantrolene General and Local Anesthetics Abenezer Aklog  General Anesth cont... 36  Specific inhalational Anesthetics  Isoflurane  Nonflammable nonexplosive volatile liquid at room To  Commonly used inhalational anesthetic worldwide  Pharmacokinetics  Has a blood:gas partition coefficient substantially lower than that of halothane or enflurane. So rapid induction and recovery  More than 99% of inhaled isoflurane is excreted unchanged via the lungs  0.2% is oxdatively metabolized by CYP2E1  Doesn’t appear to be a mutagen, teratogen, or carcinogen General and Local Anesthetics Abenezer Aklog  General Anesth cont... 37  Specific inhalational Anesthetics  Clinical Use  Typically used for maintenance of anesthesia  Pungent odor cause breath holding, coughing (not suitable for induction)  Inhaled conce. of 1%–2% (~1–2 MAC) used for maintenance of anesthesia  Adjunct agents such as opioids or nitrous oxide reduces the concentration  Side Effects o CVS  Conce. dependent decrease in arterial blood pressure by dec. PVR  Unlike halothane, CO is maintained General and Local Anesthetics Abenezer Aklog  General Anesth cont... 38  Specific inhalational Anesthetics  Side Effects o Respiratory system  Conce, dependent depression of ventilation (reduce Tidal volume)  Depress the ventilatory response to hypercapnia and hypoxia  Bronchodilator but airway irritant (stimulate airway reflexes-cough) o Nervous system  It dilates the cerebral vasculature, producing increased cerebral blood flow and the risk of increased ICP but less than produced by halothane  Preferred agent for neurosurgical procedures General and Local Anesthetics Abenezer Aklog  General Anesth cont... 39  Specific inhalational Anesthetics  Side Effects o Muscle  Produces some relaxation of skeletal muscle via its central effects  Enhances the effects of both depolarizing and nondepolarizing muscle relaxants  More potent than halothane in its potentiation of NMB agents  Relaxes uterine smooth muscle and is not recommended for analgesia or anesthesia for labor and vaginal delivery General and Local Anesthetics Abenezer Aklog  General Anesth cont... 40  Specific inhalational Anesthetics  Enflurane  Nonflammable nonexplosive colorless volatile liquid at room To  Pharmacokinetics  Has relatively high blood:gas partition coefficient  Induction of anesthesia and recovery from enflurane are relatively slow  2%–8% of absorbed enflurane undergoing oxidative metabolism by hepatic CYP2E1  DDI- Patients taking isoniazid exhibit enhanced metabolism of enflurane  Elevate serum fluoride concentrations General and Local Anesthetics Abenezer Aklog  General Anesth cont... 41  Specific inhalational Anesthetics  Clinical Use  Primarily utilized for maintenance rather than induction of anesthesia  Ability to decrease seizure threshold and potentially produce nephrotoxicity have limited its clinical utility  Side effects o CVS  Causes a conce. dependent decrease in arterial blood pressure (by Dec. CO)  Has minimal effects on heart rate (neither Brady nor Tachycardia) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 42  Specific inhalational Anesthetics  Side effects o Respiratory system  Produces a greater depression of the ventilatory responses to hypoxia and hypercarbia than Halothane/Isoflurane o Nervous system  Like other halogenated IA, increases cerebral blood flow and ICP  Has an unusual property of producing electrical seizure activity  Not used in patients with seizure disorders General and Local Anesthetics Abenezer Aklog  General Anesth cont... 43  Specific inhalational Anesthetics  Side effects o Muscle  Produces significant skeletal muscle relaxation in the absence of muscle relaxants and relaxes uterine smooth muscle  Significantly enhances the effects of nondepolarizing muscle relaxants o Renal system  Metabolic products (Fluoride ions) may rarely cause nephrotoxicity with prolonged exposure General and Local Anesthetics Abenezer Aklog  General Anesth cont... 44  Specific inhalational Anesthetics  Desflurane  Nonflammable nonexplosive highly volatile liquid at room To  Pharmacokinetics  Has a very low blood:gas partition coefficient (0.42)  Not very soluble in fat or other peripheral tissues  Alveolar (and blood) conce. rapidly rises to the level of inspired conce Rapid rate of rise of FA/FI (rapid induction)  Emergence from anesthesia also is very rapid  More than 99% is eliminated unchanged via the lung General and Local Anesthetics Abenezer Aklog  General Anesth cont... 45  Specific inhalational Anesthetics  Clinical Use  Widely used for outpatient surgery (b/c of rapid recovery)  Irritates the tracheobronchial tree and can provoke coughing  Therefore, Anesthesia is induced with IV agents and maintained with it  Side Effects o CVS  Produces hypotension primarily by decreasing PVR  Cardiac output is well preserved General and Local Anesthetics Abenezer Aklog  General Anesth cont... 46  Specific inhalational Anesthetics  Side Effects o Respiratory system  Causes a conce-dependent increase in respiratory rate and a decrease in tidal volume  Result in elevated arterial CO2 tension o Nervous system  Produces an increase in cerebral blood flow and ICP  Increases in ICP can be prevented by hyperventilation General and Local Anesthetics Abenezer Aklog  General Anesth cont... 47  Specific inhalational Anesthetics  Sevoflurane  Nonflammable nonexplosive clear, colorless volatile liquid at room To  Pharmacokinetics  Has low blood:gas partition coefficient  Not soluble in blood or other peripheral tissues  Alveolar (and blood) conce. rapidly rises to the level of inspired conce Rapid rate of rise of FA/FI (rapid induction)  Emergence from anesthesia also is very rapid  About 3-5% is metabolized in the liver by CYP2E1 General and Local Anesthetics Abenezer Aklog  General Anesth cont... 48  Specific inhalational Anesthetics  Clinical use  Widely used for outpatient anesthesia (for induction and maintenance)  Has properties that make it an ideal induction agent: pleasant smell, rapid onset, and lack of irritation to the airway  Side Effects o CVS  Cause Hypotension due to systemic vasodilation and decrease in CO  Doesn’t produce tachycardia and thus may be a preferable agent in patients prone to myocardial ischemia General and Local Anesthetics Abenezer Aklog  General Anesth cont... 49  Specific inhalational Anesthetics  Side Effects o Respiratory system  Produces a conce-dependent reduction in tidal volume and increase in respiratory rate  Most effective clinical bronchodilator of the inhalational anesthetics o Nervous system  Effects on cerebral vascular resistance, CMRo2, and CBF that are similar to Isoflurane and Desflurane  Associated with delirium on emergence from anesthesia in children General and Local Anesthetics Abenezer Aklog  General Anesth cont... 50  Specific inhalational Anesthetics  Side Effects o Muscle  Produces skeletal muscle relaxation and enhances the effects of nondepolarizing and depolarizing NMBs o Renal system  Controversy has surrounded the potential nephrotoxicity of Compound A  Cpd A is produced by interaction of sevoflurane with the CO2 absorbent soda lime  FDA recommends that sevoflurane be administered with fresh gas flows of 1–2 L/min for short period of time General and Local Anesthetics Abenezer Aklog  General Anesth cont... 51  Specific inhalational Anesthetics  Nitrous Oxide (“Laughing Gas”)  Nonflammable nonexplosive Colorless, odorless gas at room To  Pharmacokinetics  Very insoluble in blood and other tissues (FA/FI~1)  Provides for rapid induction of anesthesia and rapid emergence ff D/C  Rapid uptake of N2O from alveolar gas serves to concentrate coadministered halogenated anesthetics  This effect (the “Second gas effect") speeds induction of anesthesia General and Local Anesthetics Abenezer Aklog  General Anesth cont... 52  Specific inhalational Anesthetics  Pharmacokinetics  On D/C, N2O can diffuse from blood to the alveoli, diluting O2 in the lung  This can produce an effect called diffusional hypoxia (Mgt- 100%O2)  About 99.9% of N2O is eliminated in unchanged form by the lungs  Clinical Use  Potent analgesic but a weak anesthetic effect  Deep levels of anesthesia are unattainable even at highest possible conce.  Analgesic effect occur even at low conce (20%) mediated by activation of opioidergic neurons in the periacqueductal gray matter General and Local Anesthetics Abenezer Aklog  General Anesth cont... 53  Specific inhalational Anesthetics  Side Effects o CVS  Has stimulatory effects on the sympathetic nervous system  CV effects are influenced by co-administered anesthetic agents  With H IA – It increases HR, ABP, and CO  With Opioids –It decreases ABP, and CO  N2O also increases venous tone in both the peripheral and pulmonary vasculature  Not indicated for pts with preexisting pulmonary hypertension General and Local Anesthetics Abenezer Aklog  General Anesth cont... 54  Specific inhalational Anesthetics  Side Effects o Respiratory system  Causes modest increases in respiratory rate and decreases in tidal volume  Depress the ventilatory response to hypoxia (Monitor arterial O2 saturation) o Nervous System  Significantly increase CBF and ICP (by Vasodilation)  Vasodilation is significantly attenuated by the simultaneous admin. of IV agents such as Opiates and Propofol  Combination of N2O and inhaled agents results in greater Vasodilation General and Local Anesthetics Abenezer Aklog  General Anesth cont... 55  Specific inhalational Anesthetics  Side Effects o Muscle  Unlike H IA, N2O doesn’t relax skeletal muscle, enhance effect of NMB, nor does it cause Malignant Hyperthermia o Other S/E  Interacts with the cobalt of Vitamin B12, thereby preventing vitamin B12 from acting as a cofactor for Methionine synthase  Produce signs of vitamin B12 deficiency, including megaloblastic anemia and peripheral neuropathy Risk is high in alcoholics, malnourished, and Vit B12 deficient pts General and Local Anesthetics Abenezer Aklog  General Anesth cont... 56 Intravenous Anesthetics (IV A)  Used to facilitate rapid induction of anesthesia (fast onset of action)  Replaced inhalation as the preferred method of anesthesia induction  With the introduction of Propofol, IV A also became a good option for the maintenance of anesthesia (rapid return to preoperative mental status)  Currently available IV A are not ideal anesthetic drugs  Comb with Inhaled anesthetics, sedative-hypnotics, opioids, NMB drugs  IV A used for induction of general anesthesia are lipophilic  Preferentially partition into highly perfused lipophilic tissues (brain) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 57 Intravenous Anesthetics (IV A)  Termination of anesthesia after single boluses of parenteral anesthetics primarily reflects redistribution out of the CNS rather than metabolism  After redistribution, anesthetic blood level is determined by the metabolic rate and amount and lipophilicity of stored anesthetic in the tissue  Thus, parenteral anesthetic half-lives are “context sensitive,”  E.g. single bolus Thiopental- emergence with in 10min, but with prolonged admin. Emergence require more than a day  Most individual variability in sensitivity to parenteral anesthetics can be accounted for by pharmacokinetic factors (esp Distribution) General and Local Anesthetics Abenezer Aklog  Context-sensitive half-time of IV general anesthetics. 58 The duration of action of single intravenous doses of anesthetic/hypnotic drugs is similarly short for all and is determined by redistribution of the drugs away from their active sites. However, after prolonged infusions, drug half lives and durations of action are dependent on a complex interaction between the rate of redistribution of the drug, the amount of drug accumulated in fat, and the drug’s metabolic rate. This phenomenon has been termed the context sensitive half- time; that is, the t1/2 of a drug can be estimated only if one knows the context— the total dose and over what time period it has been given. Note that the half-times of some drugs such as etomidate, propofol, and ketamine increase only modestly with prolonged infusions; others (e.g., diazepam and thiopental) General and Local Anesthetics Abenezer Aklog increase dramatically.  General Anesth cont... 59  Specific Intravenous Anesthetics  Propofol/Fospropofol  Most commonly used IV A for induction of anesthesia (replaced barbiturates)  Propofol is formulated for IV administration as a 1% (10-mg/mL) emulsion  Associated with significant pain on injection and hyperlipidemia  Fospropofol, a new aqueous formulation of propofol, is not associated with these adverse effects  Fospropofol is a phosphate ester prodrug of propofol  Hydrolyzed by endothelial alkaline phosphatases to yield propofol, phosphate, and formaldehyde General and Local Anesthetics Abenezer Aklog  General Anesth cont... 60  Specific Intravenous Anesthetics  Pharmacokinetics  Has a context-sensitive t1/2 of about 10min with an infusion lasting 3h and about 30min for infusions lasting up to 8h  Shorter duration of action after infusion can be explained by its very high clearance (Hepatic and nonhepatic [30% in lung])  Metabolized in the liver by conjugation to sulfate and glucuronide  Highly protein bound (PK affected by conditions altering serum protein)  Clearance is reduced in the neonates and elderly but increased in young children General and Local Anesthetics Abenezer Aklog  General Anesth cont... 61  Specific Intravenous Anesthetics  Clinical use  B/c of reasonably short elimination t1/2, it often is used for maintenance of anesthesia as well as for induction  Induction dose of propofol in a healthy adult is 2–2.5 mg/kg  Dosages should be reduced in the elderly and in the presence of other sedatives and increased in young children.  Sedating doses of propofol are 20%–50% of those required for general anesthesia  Has a significant antiemetic action (dec, postoperative nausea and vomiting) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 62  Specific Intravenous Anesthetics  Side Effects o Nervous System  Produce sedating and hypnotic effects via GABAA R  Suppresses the EEG, and, in sufficient doses, can produce burst suppression of the EEG (used in the management of Status epilepticus)  Decreases the CMRo2, CBF, and intracranial and intraocular pressures  Animal studies suggests that it has a neuroprotective effects during focal ischemia General and Local Anesthetics Abenezer Aklog  General Anesth cont... 63  Specific Intravenous Anesthetics  Side Effects o CV System  Produces a dose-dependent decrease in BP (both dec in PVR & CO)  Inhibit the normal baroreflex response and thus sympathetic activity o Respiratory System  Potent respiratory depressant and generally produces apnea after induction  Monitor pts to ensure adequate oxygenation and ventilation  Doesn’t provoke bronchospasm thus suitable in asthmatic pts General and Local Anesthetics Abenezer Aklog  General Anesth cont... 64  Specific Intravenous Anesthetics  Side Effects o Other side effects  Pain on injection–minimized by co-administration with Lidocaine  Associated with rare but potentially fatal complication, PRIS, (Propofol Infusion Syndrome)  Chxed by Metabolic acidosis, Rhabdomyolysis, Hyperlipidemia, LFT  Poses high risk of bacterial infection (Discard after 6hrs once opened)  B/c it is supplied in a mixture of soybean oil, glycerol, and egg lecithin - an excellent media for bacterial growth General and Local Anesthetics Abenezer Aklog  General Anesth cont... 65  Specific Intravenous Anesthetics  Barbiturates  Thiopental and Methohexital are used for induction of general anesthesia  Mixing barbiturates with drugs in acidic solutions during anesthetic induction can result in precipitation of the barbiturate as the free acid  Standard practice is to delay the administration of other drugs until the barbiturate has cleared the intravenous tubing  Pharmacokinetics  Thiopental and Methohexital undergo hepatic metabolism  Mostly by oxidation but also by N-dealkylation, desulfuration and destruction of the barbituric acid ring structure General and Local Anesthetics Abenezer Aklog  General Anesth cont... 66  Specific Intravenous Anesthetics  Pharmacokinetics  Methohexital differ in its much more rapid clearance  Thus, it accumulates less during prolonged infusions  B/c of its slow elimination and large volumes of distribution, thiopental can produce unconsciousness lasting several days (not for maintenance)  Liver cirrhosis result in prolongation of the clinical action of barbiturates  Are highly protein bound  Initial free concentration and hypnotic effect of an induction dose increases in pts with reduced serum protein level General and Local Anesthetics Abenezer Aklog  General Anesth cont... 67  Specific Intravenous Anesthetics  Clinical use  Thiopental (3–5 mg/kg IV) or Methohexital (1–1.5 mg/kg IV) induce anesthetic effect (unconsciousness) with in 30seconds  Neonates and infants require higher induction dose than elderly & pregnant – rapid metabolism in neonates and infants  In mentally challenged patients and uncooperative pediatric patients  Barbiturates such as methohexital (20–30 mg/kg) may be administered per rectum to facilitate induction of anesthesia  Doses can be reduced by 10-50% after premedication with benzodiazepines, opiates, or ἀ2 adrenergic agonists –hv additive hypnotic effect General and Local Anesthetics Abenezer Aklog  General Anesth cont... 68  Specific Intravenous Anesthetics  Side Effects o Nervous system  Dose dependent decrease CMRo2, CBF, and ICP  Useful in the mgt of pts with space-occupying intracranial lesions  May provide neuroprotection from focal cerebral ischemia in neurosurgery  Barbiturates, except methohexital, decrease electrical activity on the EEG  Can be used as anticonvulsants  Methohexital activates epileptic foci (facilitate Electroconvultion therapy) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 69  Specific Intravenous Anesthetics  Side Effects o CV system  Produce dose-dependent decreases in BP (Dec. PVR –venodilation)  Less pronounced inhibition of baroreflexes. Hence compensatory inc. in HR  Hypotension can be severe in patients with an impaired ability to compensate for venodilation (pts with hypovolemia, cardiomyopathy, VHD, CAD) o Respiratory system  Cause respiratory depression by decreasing minute ventilation and tidal volume General and Local Anesthetics Abenezer Aklog  General Anesth cont... 70  Specific Intravenous Anesthetics  Side Effects o Respiratory system  Reflex responses to hypercarbia and hypoxia are diminished  Compared to Propofol, produce a higher incidence of wheezing in asthmatics, due to histamine release from mast cells during induction of anesthesia o Other side effects  Can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria (Contraindicated in this pts)  Abdominal pain and mental confusion General and Local Anesthetics Abenezer Aklog  General Anesth cont... 71  Specific Intravenous Anesthetics  Etomidate  An IV A with hypnotic but not analgesic effects  Often chosen for its minimal hemodynamic effects (greater margin of safety)  Pharmacokinetics  Induction dose produces rapid onset of anesthesia  Rapidly hydrolyzed in the liver to inactive compound (short Elimination t1/2) Elimination is both renal (78%) and biliary (22%).  Highly protein bound (77%), primarily to albumin General and Local Anesthetics Abenezer Aklog  General Anesth cont... 72  Specific Intravenous Anesthetics  Clinical Use  Primarily used for anesthetic induction of patients at risk for hypotension.  Induction dose (0.2–0.3 mg/kg IV) are associated with pain on injection and myoclonic movement (Mgt- Lidocaine and BZD, respectively)  Side Effects o Nervous system  Decrease CMRo2, CBF, ICP  Produces increased EEG activity in epileptogenic foci and has been associated with seizures General and Local Anesthetics Abenezer Aklog  General Anesth cont... 73  Specific Intravenous Anesthetics  Side Effects o CV system  Produce a small increase in HR and little or no decrease in BP or CO  Useful for patient with compromised myocardial oxygen or blood supply or both o Respiratory System  Produce less degree of respiratory depression than thiopental  Depression exaggerated when combined with inhaled anesthetics or opioids  Apnea may occasionally follow rapid intravenous injection General and Local Anesthetics Abenezer Aklog  General Anesth cont... 74  Specific Intravenous Anesthetics  Side Effects o Other side effects  Has been associated with nausea and vomiting  Also causes adrenocortical suppression  By dose-dependent inhibition of 11β-hydroxylase, an enzyme necessary for the conversion of cholesterol to cortisol  B/c of its endocrine effects, it is not used as continuous infusion  Ultrashort-acting analogue, methoxycarbonyl-etomidate doesn’t produce adrenocortical suppression General and Local Anesthetics Abenezer Aklog  General Anesth cont... 75  Specific Intravenous Anesthetics  Ketamine  Partially water-soluble and highly lipid-soluble phencyclidine derivative  Differ from other IV A in its ability to produce significant analgesia  Supplied as a mixture of the R+ and S- isomers even though the S- isomers is more potent and has less side effects  Pharmacokinetics  High lipid solubility ensures a rapid onset of its effect  Hepatically metabolized to norketamine (less active) by CYPs (3A4,2B6)  Which is then Hydroxylated and excreted in urine and bile General and Local Anesthetics Abenezer Aklog  General Anesth cont... 76  Specific Intravenous Anesthetics  Pharmacokinetics  Large volume of distribution and rapid clearance make it suitable for continuous infusion  The only IV A that has low protein binding  Clinical Use  Useful for anesthetizing patients at risk for hypotension and bronchospasm  Rapidly produces a hypnotic state quite distinct from that of other anesthetics General and Local Anesthetics Abenezer Aklog  General Anesth cont... 77  Specific Intravenous Anesthetics  Clinical Use  Pts have profound analgesia, unresponsiveness to commands, and amnesia but may have their eyes open, move their limbs involuntarily, and breathe spontaneously  This cataleptic state has been termed “Dissociative anesthesia”  Shown to reduce the development of tolerance to long-term opioid use  Can be administered IV, IM, P.O, or rectally (imp’t for mentally challenged pt  Does not elicit pain on injection or true excitatory behavior as described for methohexital General and Local Anesthetics Abenezer Aklog  General Anesth cont... 78  Specific Intravenous Anesthetics  Side Effects o Nervous System  Has indirect sympathomimetic activity  Cataleptic state is accompanied by nystagmus with pupillary dilation, salivation, and lacrimation (mgt- premedicate with anticholinergics)  Unlike others, it increases CBF and ICP with minimal alteration of cerebral metabolism (attenuated by coadm. With sedative-hypnotic agents)  Emergence delirium, characterized by hallucinations, vivid dreams, and delusions –result in postoperative pt dissatisfaction (mgt- BZD) General and Local Anesthetics Abenezer Aklog  General Anesth cont... 79  Specific Intravenous Anesthetics  Side Effects o CV System  Produce transient but significant increases in BP, HR, and CO  Via Inhibition of both central and peripheral catecholamine reuptake  Increases myocardial O2 consumption and is not an ideal drug for patients at risk for myocardial ischemia o Respiratory System  Respiratory depression is less severe  Produce bronchodilation thus imp’t for pts at risk of bronchospasm General and Local Anesthetics Abenezer Aklog 80 Local Anesthetics General and Local Anesthetics Abenezer Aklog  Local Anesthetics 81  Local anesthesia refers to loss of sensation in a limited region of the body  Accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation  LA cause both sensory and motor paralysis in the area innervated  With local anesthesia the drug is delivered directly to the target organ  Systemic circulation serves only to diminish or terminate LA effect  Recovery is normally spontaneous, predictable, and without residual effects General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 83 The ideal local anesthetic has  Low systemic toxicity at an effective concentration  Quick onset of action  Duration of action should be sufficient to allow time for the surgical procedure  It should be soluble in water and stable in solution  It should not deteriorate by the heat of sterilization  It should be effective both when injected into tissue and when applied topically to mucous membranes  Its effect should be completely reversible General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 84 Chemistry of LA Typical local anesthetic agents contain Hydrophobic /lipophilic group (must be Aromatic ring) Hydrophilic- Amine (20 /30) substituents /ionizable group Connected by an intermediate ester or amide linkage General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 85  Pharmacokinetics A. Absorption  Systemic absorption of injected LA from the site of administration is determined by  Dosage  Site of Injection High from intercostal nerves & bronchial mucosa than femoral/sciatic  Drug-Tissue binding  Local tissue blood flow  Use of Vasoconstrictors (e.g. Epinephrine)- dec. absorption & inc. duration  Physicochemical property of the drug- decreases with Lipophilicity General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 86  Pharmacokinetics B. Distribution  LA are usually injected directly at the site of the target organ  Local distribution w/in this compartment is essential for clinical effect  Systemic distribution has two phases  Initial Phase- rapid distribution in blood and highly perfused organs  Second Phase- distribution into less well perfused tissue (muscle & gut)  Potential toxicity of the LA is affected by the protective effect afforded by uptake by the lung  Serve to attenuate the arterial concentration General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 87  Pharmacokinetics C. Metabolism and Excretion  Metabolism of LA depends on whether the cpd has Ester or Amide link  Ester type LA are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase (Psuedocholinesterases)  The amide LA undergo complex biotransformation in the liver, which includes hydroxylation and N-dealkylation by CYPs  Considerable variation in the rate of liver metabolism of individual amide  Prilocaine (fastest) > Lidocaine > Mepivacaine > Ropivacaine ≈ Bupivacaine and levobupivacaine (slowest) General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 88  Pharmacokinetics C. Metabolism and Excretion  Toxicity from amide-type LA is more likely to occur in patients with hepatic disease E.g. t1/2 of Lidocaine increase from 1.6 to 6 hrs in pts with liver disease  Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with heart failure  The metabolites of amide and ester are excreted in the urine  Acidification of urine promotes ionization leading to more rapid elimination General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 89  Pharmacodynamics  LAs block voltage-gated Na+ channel  Na+ channel function alteration Batrachotoxin, veratridine and scorpion venoms  Prevent inactivation of the channel (prolonged influx of Na+)  Tetradotoxin and saxitoxin  Block Na+ channel near the extracellular region  Local anesthetics Block by bind to the intracellular component of the channel General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 90  Pharmacodynamics  LAs block the initiation & propagation of action potentials by preventing the voltage-dependent increase in Na+ conductance  Ionization of LAs is of critical importance because the cationic form is the most active at the receptor site  However, the uncharged form is important for cell penetration as the receptor site for LAs is at the inner vestibule of the Na+ channel  After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel  Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway General and Local Anesthetics Abenezer Aklog  Paths of local anesthetic (LA) to 91 receptor sites. Extracellular anesthetic exists in equilibrium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane General and Local Anesthetics Abenezer Aklog (hydrophobic pathway) 92 General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 93  Toxicity  LA toxicity derives from two distinct processes: 1. Systemic effect from inadvertent IVascular admn or Absorption 2. Local neurotoxicity  Systemic Toxicity o CNS  Initially, LAs may cause CNS stimulation (restlessness, tremor, and even convulsion)  Selective depression of inhibitory neurons likely accounts for the excitatory phase  Convulsion is managed with IV benzodiazepines General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 94  Systemic Toxicity o CNS  Central stimulation is followed by depression; death usually is caused by respiratory failure- Mgted with ventilator and circulatory support  Due to Depression of all excitatory and inhibitory neurons o CVS  LAs decrease electrical excitability, conduction rate, and force of contraction of the Myocardium  Most LAs cause arteriolar dilation  Cardiotoxicities are seen only after high systemic concentrations are attained and CNS symptoms are evident General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 95  Commonly used local anesthetics & their applications  Esters o Cocaine  As LA, it block nerve impulses and has local vasoconstrictor effect  Its clinical use is largely restricted to topical anesthesia for ear, nose, and throat procedures (b/c of toxicity and potential for abuse)  Epinephrine plus cocaine, although still used occasionally, is hazardous  Catecholamine potentiates the cardiovascular toxicity (e.g., arrhythmia, ventricular fibrillation) of cocaine  Over dosage leads to convulsions followed by CNS depression General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 96  Commonly used local anesthetics & their applications  Esters Procaine o Chloroprocaine  Chlorinated derivative of procaine with rapid onset and short duration of action  Widespread use as an epidural agent in obstetrical anesthesia  Rapid hydrolysis served to minimize risk of systemic toxicity or fetal exposure  Chloroprocaine that contain calcium EDTA as the preservative, may cause muscular back pain (might be due to tetany) General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 97  Commonly used local anesthetics & their applications  Esters o Tetracaine  Significantly more potent and has a longer duration of action than procaine  May exhibit increased systemic toxicity because it is more slowly metabolized  Widely used in spinal anesthesia when a drug of long duration is needed  Rarely used in peripheral nerve blocks because of the large doses often necessary, its slow onset, and its potential for toxicity General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 98  Commonly used local anesthetics & their applications  Amides o Lidocaine  Is the prototypical amide local anesthetic  Produces faster, more intense, longer-lasting, and more extensive anesthesia than equal conce. of procaine  Is an alternative choice for individuals sensitive to ester-type LAs  A transdermal patch is used for relief of pain associated with postherpetic neuralgia General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 99  Commonly used local anesthetics & their applications  Amides  Pharmacokinetics  Absorbed rapidly after parenteral administration and from the GI and respiratory tracts  Epinephrine decreases the rate of absorption and thus decrease systemic toxicity and prolongs its duration of action  Is dealkylated in the liver by CYPs to monoethylglycine xylidide and glycine xylidide  75% of xylidide is excreted in the urine General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 100  Commonly used local anesthetics & their applications  Amides  Toxicity  Side effects of lidocaine seen with increasing dose include  Drowsiness, Tinnitus, Dizziness, and Twitching  As the dose increases, seizures, coma, and respiratory depression and arrest will occur  Clinical Use  Widely used when a drug of intermediate duration is needed  Also used as an antiarrhythmic agent  Should not be used for spinal anesthesia b/c of Transient neurologic syndrome General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 101  Commonly used local anesthetics & their applications  Amides o Bupivacaine  Widely used potent agent capable of producing prolonged anesthesia  Its long duration of action plus its tendency to provide more sensory than motor block  Made it a popular drug for providing prolonged analgesia during labor or the postoperative period  Continuous infusions can be used to provide several days of effective analgesia General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 102  Commonly used local anesthetics & their applications  Amides  Pharmacokinetics  More slowly absorbed than lidocaine, so plasma levels increase more slowly  Primarily metabolized in the liver by CYP3A4 to pipecolylxylidine, which is then glucuronidated and excreted  Toxicity  More cardiotoxic than equieffective doses of lidocaine  Manifested by severe ventricular arrhythmias and myocardial depression after inadvertent IV admin. General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 103  Commonly used local anesthetics & their applications  Amides  Toxicity  Although lidocaine and bupivacaine both rapidly block cardiac Na+ channels during systole  Bupivacaine dissociates much more slowly than lidocaine during diastole  Bupivacaine-induced cardiac toxicity can be enhanced by coexisting acidosis, hypercarbia, and hypoxemia  Emphasizing the importance of prompt airway control  Lipid emulsion infusion may also be used to Tx cardiotoxicity. General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 104  Commonly used local anesthetics & their applications  Amides o Mepivacaine  An intermediate acting amide LA  Pharmacologically resembles lidocaine except it has vasoconstrictor effect  More toxic to the neonate and thus is not used in obstetrical anesthesia  B/c of lower pH of neonatal blood and its pKa, Ion trapping occurs rather than reduced metabolism in neonates  Is not effective as a topical anesthetic General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 105  Commonly used local anesthetics & their applications  Amides o Ropivacaine  Slightly less potent than bupivacaine in producing anesthesia but has similar long duration of action  Produce less cardiotoxicity than bupivacaine  Appears to be suitable for both epidural and regional anesthesia  It seems to be even more motor-sparing than bupivacaine  Popular choice for epidural infusions for control of labor and postoperative pain General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 106  Commonly used local anesthetics & their applications  Amides o Articaine  Has both amide and ester linkage  Hydrolysis of the ester linkage terminates its action  Exhibits rapid onset (1–6 min) and duration of action of about 1h  Mainly used for dental and periodontal procedures General and Local Anesthetics Abenezer Aklog  Local Anesth cont... 107  Commonly used local anesthetics & their applications  Amides o Prilocaine  An intermediate-acting amino amide with pharmacological profile similar to that of lidocaine (except Vasoconstriction)  Its use is largely limited to dentistry b/c of its propensity to cause methemoglobinemia  Results from accumulation of one of its metabolites, ortho-toluidine, an oxidizing agent  If necessary, it is treated by the intravenous administration of methylene blue (1–2 mg/kg). General and Local Anesthetics Abenezer Aklog