Anesthesia Pharmacology PDF

Pharmacolo gy in general and regional anesthesia Alicja Bartkowska-Śniatkowska MD PhD Anaesthesia – word derived from the Greek. It means insensible or without feeling. The Greek philosopher Dioscorides first used the term anaesthesia in the first century AD to desribe the narcotic-like effec...

Pharmacolo gy in general and regional anesthesia Alicja Bartkowska-Śniatkowska MD PhD Anaesthesia – word derived from the Greek. It means insensible or without feeling. The Greek philosopher Dioscorides first used the term anaesthesia in the first century AD to desribe the narcotic-like effects of the plant mandragora.  The short history of anesthesia The first general anesthetic was diethyl ether and it was originally prepared in 1540 by Valerius Cordus. Ether was used as anesthetic agent in 1842 by Crawford W. Long and Wiliam E. Clark and they used it on patients for surgery and dental extraction. The modern local anesthesia was created by Carl Koller. History of the inhalational anesthetic agent  Anesthesia General Regiona l Topical Inhalational (cream, lotion, – gas or liquid liquid or spray) Intravenous Parenteral (spinal, epidural, infiltration, nerve block)  The basic Triad of general anesthesia are Uncoscousness Analgesia Muscle relaxation Amnesia or loss of awareness No stress autonomic response No movement in response to surgical stimuli  Anesthesia - steps  Induction – putting asleep  Maintenance – keeping the patient asleep  Reversal – waking up the patient  Induction of anesthesia Goal: Rapidly, safely, and pleasantly produce hypnosis, amnesia, analgesia, akinesia, and autonomic and sensory block in patients undergoing surgery while maintaining hemodynamic stability and ventilation IV induction ○ With endotracheal intubation ○ With supraglottic airway placement Inhalation induction ○ Most commonly used in young children  Inhalation Induction Administered by gas mask - most commonly used in younger children ○ Prevents IV needle trauma in awake children with fear of needles and pain ○ Not advised in patients at risk of cardiovascular problems or who may need rapid intubation therefore IV induction is advised in the following: Obesity Risk of aspiration Achalasia, pyloric stenosis, recent nausea and vomiting Risk of malignant hyperthermia Goal: Smooth, atraumatic experience of anesthesia ○ Rapid induction of unconsciousness ○ Avoiding overdose of anesthetic agents. Children are at increased risk of hypotension ○ Bradycardia increases risk  It is achieved through airway tract Equipment: facemask, laryngeal mask and endotracheal tube The agent: gas  MAC – Minimal Alveloar Concentration MAC that concentration required to prevent 50 % of patients moving when subjected to standart midline incision  Inhalation - Physiology and Drugs Generally works faster in healthy children than in Nitrous oxide ○ Well tolerated in children adults ○ Primary or adjunct inhalant No noxious smell Faster cardiac output speeds uptake of inhalants If given before more noxious gases can reduce ○ Higher proportion of output distributed to aversion response brain and solid organs Sevoflurane Organs of pharmacological effect ○ Most commonly used agent in US Faster respiratory rate leads to more rapid ○ Less pungent/noxious smell distribution ○ Less irritating to airway CO and BP dependant on HR and preload Decreased risk of laryngospasm or other ○ problems Less compliant ventricles than adults ○ Bradycardia not well tolerated Desflurane ○ Less often used due to increase risk of airway problems Halothane ○ No longer used in US, Europe due to hepatotoxicity ○ Still used worldwide in children ○ Strong myocardial depression Especially worrisome in infants ○ Use with atropine  NITROUS OXIDE Colorless, odorless, nonexplosive, nonflammable Tendency to stimulate the sympathetic nervous system Increases respiratory rate and decreases tidal volume Increases cerebral blood volume and produces a mild elevation of intracranial pressure Increases cerebral oxygen consumption No significant muscle relaxation It can be used to start or maintain anesthesia  HALOTHANE Nonflammable and nonexplosive Myocardial depression, decrease blood pressure and cardiac output Rapid, shallow breathing Liver transaminase elevation It is no longer available in Poland. It can be used in developing countries It was historically used to start or maintain anesthesia  ISOFLURANE Nonflammable, pungent ethereal odor Good bronchodilator Increases cerebral blood flow and intracranial pressure Relaxes skeletal muscles Can reduce total hepatic blood flow It can be used to maintain anesthesia  SEVOFLURANE Nonpungency and rapid increases in alveolar Mildly depresses myocardial contractility Reverses bronchospasm Increases cerebral blood flow and intracranial pressure Excellent choice for smooth and rapid inhalation induction in pediatric and adult patients  DESFLURANE Very similar structure to that of isoflurane Wakeup times are almost 50% less than those observed following isoflurane The effects are similar to those of isoflurane It can be used to maintain anesthesia  Inhalation induction techniques There are some variations dependant on the age of children undergoing surgery Infants and neonates ○ Easily irritated by mask, no need to cover bad smelling gas Gradually place mask over face 5% sevoflurane with or without 70% NO Toddlers ○ Similar to infants, can apply several breaths of NO before more noxious gas ○ Can apply pleasant smelling ointment or balm to mask to help cover smell of gas School age children ○ Can be engaged by fun stories or anecdotes to make mask seem less scary ○ Can apply good smelling ointment and administer sevo with or after NO Teens ○ Similarly to school age children ○ Can start with NO and then be further inducted via IV Once the child has reached Stage III the concentration of sevoflurane should be reduced to minimum alveolar concentration level ○ Closer to 3 percent ○ Stage III signs: slower, regular rate of respiration; decreased HR; cessation of muscle movements; eyes midline ○ Administering propofol with 2 to 3 mg/kg after IV catheter placed helps achieve depth of sevoflurane anesthesia necessary for endotracheal intubation 21  IV induction - drugs Propofol Fentanyl ○ Widely used in patients of all ages ○ Used adjunctly (1 to 2 mcg/kg) to minimise pain ○ At least 3 mg/kg in children and blunt reflexes associated with noxious Increased vol of distribution and clearance stimulation ○ monitor/use with care in premature infants ○ FDA discourages its use in younger populations Sensitivity to respiratory depression As induction agent under the age of 3 For maintenance in babies under 2 months Lidocaine For sedation in most children ○ 1 mg/kg minimises pain of propofol, blunts airway reflexes, and supplements anesthetic effects Dexmedetomidine Monitor to avoid systemic toxicity ○ 0.5 to 2 mcg/kg single or adjunct to other agents ○ Preserves respiratory drive Neuromuscular blockers ○ Unless well indicated in pediatric cases intubation can be performed without these drugs Ketamine ○ Still used in neonates to decrease dose of propofol ○ Given either IV (2mg/kg) and IM (5 to 10 mg/kg) needed and create “optimal conditions for a quick ○ Can be useful in kids who refuse mask or IV intubation” induction Give with a benzo to reduce hallucinations Succinylcholine More common in older kids ○ FDA issued black box warning in children except for emergency airway management cute rhabdomyolysis and hyperkalemia in undiagnosed muscular dystrophies  IV induction Generally children have a higher volume of distribution for IV drugs and need higher initial doses May decide to give atropine before IV induction to prevent bradycardia in neonates or wait to treat if bradycardia occurs during surgery ○ 0.02 mg/kg IV Might not be able to preoxygenate ○ Child might refuse mask or become too irritated Especially true of younger children and babies ○ High flow oxygen with mask as close to face as tolerable may help  BARBITURATES For example: thiopental Decrease blood pressure and increases heart rate Cardiac output and arterial blood pressure may fall dramatically due to uncompensated peripheral pooling of blood and direct myocardial depression Depress the medullary ventilatory center and response to hypercapnia and hypoxia Decrease cerebral blood flow and intracranial pressure  BARBITURATES Thiopental Dose 3-7 mg/kg Effects: hypnotic, analgesic, antiepileptic  BENZODIAZEPINES Diazepam, midazolam, lorazepam Minimal cardiovascular depressant effect Decrease arterial blood pressure, cardiac output Depress the ventilatory response to CO2 Reduce cerebral oxygen consumption, cerebral blood flow and intracranial pressure Oral sedative doses often produce amnesia - useful premedication property Small doses: antianxiety, amnestic, sedative effect Higher doses: stupor, unconsciousness  KETAMINE Increases arterial blood pressure, heart rate and cardiac output Rapid intravenous bolus occasionally produces apnea Myoclonic activity associates with increased subcortical electrical activity – use during electroshock Increases cerebral oxygen consumption, cerebral blood pressure and intracranial pressure – use in patients with space-occupying intracranial lesions such as occur with head trauma  ETOMIDATE Minimal effects on the cardiovascular system Myocardial contractility and cardiac output usually unchanged Induction doses usually don’t result in apnea Decreases cerebral metabolic rate, cerebral blood flow and intracranial pressure Inhibits enzymes involved in cortisol and aldosterone synthesis  adrenocortical suppresion  PROPOFOL Decreases arterial blood pressure Factors associated with propofol-induced hypotension: large doses, rapid injection and old age Usually causes apnea following an induction dose Propofol-induced depression of upper airway reflexes (exceeds that of thiopental) allowing intubation, endoscopy or laryngeal mask placement without neuromuscular blockade Lower risk of wheezing in asthmatic or nonasthmatic patients compared with barbiturates or etomidate, although propofol can cause histamine release Dose 1- 2.5 mg/kg Effects : hypnosis Possible complications during induction Obstruction ○ Caused by: Reduction in airway tone during anesthesia Relatively large tongue ○ Prevention: Jaw thrust Maintain opening of oral or nasopharyngeal airway Continuous positive pressure with tightly sealed mask Laryngospasm ○ Can occur during induction, maintenance , or emergently in kids ○ Usually during light levels of anesthesia Analgesic Agents Paracetamol Non Steroid Anti Inflamatory Drugs Opioids  Analgesic Agents Recept Location Effects OPIOIDS l or type l Four major receptor types: mu, sigma, μ Brain, spinal Analgesia, respiratory cord depression, kappa, delta euphoria, addiction, ALL pain messages Clinical effects: l blocked analgesia, some degree of sedation κ Brain, spinal Analgesia, sedation, all non-thermal pain cord messages blocked Side effects: respiratory δ Brain Analgesia, l antidepression, depression, skeletal dependence muscle hypertonus, Analgesic Agents Analgesic Agents Opioid effects Opioid effects - summary  Analgesic Agents Opioids can be used in intraoperative anesthesia in bolus or maintenance infusion Dose ½ time of Metabolism elimination Sufentanyl 0.1 g/kg 50 min liver Fentanyl 0,5-2 g/kg 190 min liver Alfentanyl 5 – 100 g/kg 100 min liver Remifentany 0.05 – 2 g/kg 10 min Plasma and l 0.05-0.3 g/kg/min tissue esterases  Analgesic Agents  Rapid administration of larger doses of opioids (for example fentanyl and/or remifentanyl) can induce chest wall rigidity severe enough to prevent adequate „bag and mask” ventilation!!!  Treatment → neuromuscular blocking agents  Opioids can effectively blunt the bronchoconstrictive response to airway stimulation (for example during intubation) Neuromuscular blocking agents Indications for NBA?  Tracheal intubation  Surgery if muscle relaxation if essential  Mechanical ventilation  Neuromuscular blocking agents Succinylcholine  The only depolarizing muscle relaxant in clinical use today  It is also called diacetylcholine or suxamethonium  Rapid action 30-60s  Metabolized by pseudocholinesterase into succinylmonocholine,  Has short time of duration – typically less than 10 min  Succinylcholine Prolonged paralysis from succinylcholine caused by abnormal pseudocholinesterase should be treated with continued mechanical ventilation and sedation until muscle function returns to normal by clinical signs.  Succinylcholine Dose for intubation 1-1.5mg/kg  Side Effects:  Bradycardia Fasciculations (visible motor unit contractions) Muscle pain – ‘sux’ pain Transient raised pressure in eye, stomach and cranium Hyperkalemia Intraocular pressure elevation  Succinylcholine It can cause malignant hyperthermia, a hypermetabolic disorder of skeletal muscle. It appears also with exposure to inhaled general anesthetics. Mutation: ryanodine receptor (located on chromosome 19) and sodium channel on chromosome 17 Clinical manifestations: hyperthermia (can rise as much as 1OC every 5 min) increase oxygen consumption, CO2 production, increased serum myoglobin, creatine kinase Acute treatment: Dantrolene, correction of electrolyte imbalances, cooling  Neuromuscular blocking agents Nondepolarizing muscle relaxants: 1.Short acting: Mivacurium 2.Intermediate –acting: Atracurium, Cisatracurium, Vecuronium, Rocuronium 3.Long acting :Doxacurium, Pancuronium, Pipecuronium It blocks nicotinic receptors competitively resulting in inhibition of sodium channels and excitatory post-synaptic potential  Neuromuscular blocking agents Pancuronium Very commonly used as it is inexpensive. It releases noradrenaline & can cause tachycardia & hypertension. Pipercuronium It is a pancuronium derivative with no vagolytic activity, so cardiovascular stable, slightly more potent. Vercuronium (Norcuron) ́It is very commonly used now a days. It is cardiovascular stable. Shorter duration of action. It is the muscle relaxant of choice in cardiac patient. Rocuronium 8 times more potent than vecuronium and it also has earlier onset of action. Because of onset comparable to succinylcholine it is suitable for rapid sequence intubation as an alternative to succinylcholine.  Antagonists to Neuromuscular Blocking Agents Neostigmine o Acetylcholine esterase inhibitor o The effect are usually apparent in 5 min o Dose: 0.04-0.08 mg/kg o Crosses the placenta → fetal bradycardia o It is used also to treat myasthenia gravis, urinary bladder atony and paralytic ileus.  Antagonists to Neuromuscular Blocking Agents Sugammadex  Novel selective relaxant-binding agent  Available for clinical use in Europe, USA  Dose: 4-8 mg/kg  The effect are usually after 2-3 min  Atropine  Specific anticholinergic drug  As a premedication is administered intravenously or intramusculary in a range of 0.01-0.02 mg/kg  Treatment of bradyarrhythmias, bronchospasm !!!  Local anesthesia Conduction of nerve impulses is mediated by action potential (AP) generation along axon Cationic form of anesthetic binds at inner surface of Na+ channel – preventing Na+ influx (rising phase of membrane potential) which initiates AP → blockade of nerve impulses (e.g., those mediating pain)  Local anesthesia Sequence of clinical anesthesia 1) Sympathetic block (vasodilatation) 2) Loss of pain and temperature sensation 3) Loss of proprioception 4) Loss of touch and pressure sensation 5) Loss of motor function Local anesthetic drugs  Bupivacaine  Etidocaine  Lidocaine  Mepivacaine  Prilocaine  Ropivacaine  Chloroprocaine  Cocaine  Procaine  Tetracaine Regional anesthesia - what for? Rendering a specific are of the body (foot, arm, lower extremities) insensate to stimulus of surgery or other instrumentation.  Provide anesthesia for a surgical procedurę  Provide analgesia post-operatively or during labor and delivery  Diagnosis or therapy for patients with chronic pain syndromes  Topical anesthesia Application to mucous membranes: nose-, mouth-, esophagus-, tracheobronchial- genitourinary tract Commonly used:cocaine (4-10%). Unique pharmacological property – produces localized vasoconstriction as well as anesthesia Lidocaine, tetracaine  Skin surface application  Lidocaine (5%), prilocaine (2,5%)  No local irritation  No systemic toxicity  Barrier – keratinized skin layer  EMLA Eutectic Mixture of Local Anesthesics – mixture which has the lowest melting point which it is possible to obtain by the combination of the given components. Prilocaine (2,5%) + Lidocaine (2,5%) Application: venipuncture, lumbar puncture and arterial cannulation  Local infiltration  Extravascular placement of the local anesthetic in the region to be anesthetized.  For example local anesthesia in support of intravascular cannula placement.  Most common: lidocaine  Also ropivacaine, bupivacaine  Peripheral nerve block  Injecting local anesthetic near the course of a named nerve  In surgical procedures in the distribution of the blocked nerve  Relatively small dose of local anesthetic to cover large area. Peripheral nerve block Local anesthetics deposited around a peripheral nerve diffuse along a concentration gradient to block nerve fibers on the outer surface before more centrally located fibers. This accounts for early manifestations of anesthesia in more proximal areas of the extremity  Blockades Plexus Blockade  Injection of local anesthetic adjacent to plexus, e.g. cervical, brachial or lumbar plexus  In surgical anesthesia or post-operative anelgesia  Central blockades Central Neuraxial Blockade „Epidural”  Injection of local anesthetic in to the epidural space at any level of the spinal column  Anesthesia or analgesia of the thorax, abdomen, lower extremities Central Neuraxial Blockade „Spinal”  Injection of local anesthetic into CSF  Profound anesthesia of lower abdomina and extremities  Local anesthetics Lidocaine Start 5-10 min, action 60-120min Medium-acting amide Moderate vasodilatation A class 1B antiarrhythmic Duration: enhanced and peak plasma levels reduced by adrenalinę Bupivacaine Start 2-15 min, action 120-240 min Long-acting amide Prolonged cardiotoxicity in higher doses Ropivacaine Long-acting amide, 120-720 min Less duration of motor block than bupivacaine Less cardiotoxic than bupivacaine Prilocaine Medium-acting amide No vasodilatation Rapid metabolism and low toxicity It can causing methaemoglobiaesemia (important in obstetrics and anaemia!)  Vasoconstrictors – yes or no? They are added to local anaesthesia to oppose the vasodilatory action of local anesthetic agent. Warning They shouldn't be used in fingers, toes, nose and ear lobes. These are catecholamines ( epinephrine, dopamine) and noncatecholamines (phenylephrine, amphetamine, ephedrine) Summary  IV General Anesthesia Induction Drugs Sedative-Hypnotic Agents: Adjuvant Agents: Propofol Opioids ○ Widely used in patients of all ages ○ Fentanyl ○ Induction dose = 1 to 2.5 mg/kg 25 to 100 mcg, may be given in Hypovolemia or hemodynamic compromise= ≤1 divided doses mg/kg ○ Etomidate Sufentanil 0.05 to 0.1 mcg/kg, may be given in ○ For patients with hemodynamic instability ○ divided doses Induction dose = 0.15 to 0.3 mg/kg Presence of profound hypotension= 0.1 to 0.15 mg/kg Lidocaine Ketamine ○ 0.5 to 1.5 mg/kg ○ For patients with hypotension or those likely to develop For suppression of airway reflexes hypotension ○ 20 to 30 mg total ○ Induction dose = 1 to 2 mg/kg To reduce pain on injection of other Chronic use of tricyclic antidepressants= 1 mg/kg agents Presence of profound hypotension= 0.5 to 1 mg/kg Midazolam Intramuscular dose= 4 to 6 mg/kg ○ 1 to 2 mg, given in 1-mg increments Methohexital ○ For patients undergoing ECT ○ Induction dose = 1.5 mg/kg https://www.uptodate.com/contents/image?imageKey=ANEST%2F106541&topicKey=ANEST%2F94135&source=see_link https://www.uptodate.com/contents/image?imageKey=ANEST%2F102350&topicKey=ANEST%2F94135&source=see_link Inhalation Anesthetic Induction Preferred method if spontaneous breathing is Volatile Inhalation agents desired (due to mass, obstructions or compression of airway) Advantages for induction with volatile anesthetic Used if IV access cannot be obtained agents include excellent bronchodilation, dose- This method takes longer for induction than dependent decrease in skeletal muscle tone, and IV and not suitable for Rapid sequence decrease in cerebral metabolic rate of oxygen induction and intubation consumption Requires a high concentration of volatile Disadvantages include respiratory depression, anesthetic agents with the addition of N2O systemic vasodilation and decreased BP Sevoflurane All potent volatile agents can induce malignant hyperthermia Anesthetic Techniques in „specific patients” eg. geriatric, neonatal Supplemental O2 administered to reduce risk of hypoxemia because of a lower baseline of PaO2 Routine ETCO2 is also recommended even in spontaneously breathing patients due to the development of hypercapnia even when O2 saturation levels seem sufficient